ChemWiki - User contributions [en]

Levothyroxine

2007-12-06T11:54:56Z

Eyk06: Clinical pharmacology and pharmacokinetics of Levothyroxine

'''[[Introduction]]'''

'''Levothyroxine''', otherwise known as L-thyroxine, synthetic T4 or 3,5,3',5'-tetraiodo-L-thyronine, is a synthetic form of thyroxine, which is the key hormone secreted by the follicular cells of the thyroid gland. Both the naturally occuring hormone of T4 and the synthetic form exists in the L-form.

Other common brand names include ""Thyrax"", "Euthyrox", "Levaxin" and "Eltroxin" in Europe, as well as "Levoxyl" and "Synthroid" in the U.S.

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{{Drug-Box |
| Box_Name = Properties of Levothyroxine
| ImageFile = levothyroxine_v2_eyk06.gif
| IUPACName = 3,5,3',5'-Tetraiodo-L-thyronine
| OtherName = Thyrax, Euthyrox, Levaxin, Eltroxin, Levoxyl, Synthroid
| CAS_No = 51-48-9
| ATC_Code = H03AA01
| PubChem = 853
| SMILES = IC1=CC(OC2=C(I)C=C(C[C@@H](C(O)=O)N)C=C2I)=CC(I)=C1O
| Formula = C15H10I4NNaO4
| MolarMass = 798.86 g/mol (anhydrous)
| Bioavailability = approximately 100%
| Metabolism = Mainly in liver, kidneys, bones and muscles
| Half_life = approximately 7 days in healthy human bodies, 3-4 days in hyperthyroidism, 9-10 days in hypothyroidism
| Excretion = via faeces and urine
| Pregnancy_cat = A (FDA)
| Legal_status = Px (prescription only)
| Routes = Oral, intravenous
}}

'''[[Clinical Pharmacology]]'''

Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyrotropin-stimulating hormone, TSH, from the anterior pituitary,which in turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, L-thyroxine (T4) and L-triiodothyronine (T3), by the thyroid gland. Circulating serum T3 and T4 levels exert a feedback effect on both TRH and TSH secretion. When serum T3 and T4 levels increase, TRH and TSH secretion decrease. When thyroid hormone levels decrease, TRH and TSH secretion increase.

The mechanisms by which thyroid hormones exert their physiologic actions are not completely understood, but it is thought that their principal effects are exerted through control of DNA transcription and protein synthesis. T3 and T4 diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins.

Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and development, and normal maturation of the central nervous system and bone. The metabolic actions of thyroid hormones include augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins, carbohydrates and lipids. The protein anabolic effects of thyroid hormones are essential to normal growth and development.

The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.

Levothyroxine, at doses individualized according to patient response, is effective as replacement or supplemental therapy in hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.

Levothyroxine is also effective in the suppression of pituitary TSH secretion in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, Hashimoto's thyroiditis, multinodular goiter and, as adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

'''[[Pharmacokinetics]]'''

'''1. Absorption'''

Absorption of orally administered T4 from the gastrointestinal (GI) tract ranges from 40% to 80%. The majority of the Levothyroxine dose is absorbed from the jejunum and upper ileum. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybean infant formula. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption. (see Section on Precautions and Side effects)

'''2. Distribution'''

Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3. Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins.

'''3. Metabolism'''

T4 is slowly eliminated. The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately eighty-percent of circulating T3 is derived from peripheral T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (r T3). T3 and r T3 are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation.

'''4. Elimination'''

Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age.

'''[[Uses]]'''

Levothyroxine is used to treat hypothyroidism, a condition where the thyroid gland fails to produce sufficient thyroid hormone.
A body deficient in thyroid hormone cannot function properly, resulting in poor growth, slow speech, lack of energy, weight gain, hair loss, dry thick skin, and increased sensitivity to cold. When taken correctly, levothyroxine alleviates these symptoms. In addition, Levothyroxine is adminstered to treat congenital hypothyroidism (cretinism) and goiter (enlarged thyroid gland). Levothyroxine should not be used to treat weight and obesity problems.

[[Image: thyroid_gland.gif]]

'''[[Adminstration]]'''

The key objective of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state, whereas the aim of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of Levothyroxine that is adequate to achieve these goals depends on a variety of factors including the patient's age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated.Hence, the following recommendations serve only as dosing guidelines. Dosing must be individualized and adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters.

Levothyroxine is administered as a single daily dose, preferably one-half to one-hour before breakfast or other meals
to maximize its absorption. It is also recommended that the patient take the tablet with one glass of water to ease swallowing as well as to help the tablet dissolve for absorption. Also, Levothyroxine should be taken at least 4 hours apart from drugs that are known to interfere with its absorption.

Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for 4-6 weeks.

Caution should be exercised when administering Levothyroxine to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency.

'''[[Precautions and Side effects]]'''

It should be noted that there are also food and other substances that can interfere with absorption of thyroxine replacement.
Calcium and iron supplements should not be consumed within four hours of the medication. Also, soy products should be avoided within three hours of the medication, since these can lower absorption of Levothyoxine.

Synthetic Levothyroxine may result in adverse side effects such as palpitations, nervousness, headache, difficulty sleeping, insomnia, swelling of the legs and ankles, weight loss and/or increased appetite. Some may be allergic to the medicine. If the patient develops a severe reaction to the drug like difficulty breathing, shortness of breath or swelling of the face and tongue, it the patient should stop consumption and seek medical attention as soon as possible.

'''[[Synthesis of Levothyroxine]]'''

[[Image: synthesis_levothyroxine.gif]]

'''[[What is HYPERthyroidism?]]'''

'''Hyperthyroidism''' is a condition where an overactive thyroid gland produces an excessive amount of thyroid hormones, that circulate in the blood. ''("Hyper" means "over" in Greek)''. Thyrotoxicosis is a toxic condition that is caused by an excess of thyroid hormones from any cause. Thyrotoxicosis can be caused by an excessive intake of thyroid hormone or by overproduction of thyroid hormones by the thyroid gland.

'''[[What is HYPOthyroidism]]'''

'''Hypothyroidism''' refers to any state where thyroid hormone production is below normal. There are many disorders that result in hypothyroidism. These disorders may directly or indirectly involve the thyroid gland. Since thyroid hormone affects growth, development, and many cellular processes, inadequate thyroid hormone has widespread consequences for the body.

'''[[References]]'''

http://www.medicinenet.com/levothyroxine-oral/article.htm

http://en.wikipedia.org/wiki/Levothyroxine

Levothyroxine

2007-12-06T11:48:29Z

Eyk06: adminstration of Levothyroxine - updates

Levothyroxine

2007-12-06T11:40:28Z

Eyk06: Update uses of Levothyroxine

Rapamycin

2007-12-06T11:37:12Z

Eyk06: SMILES of Rapamycin inserted

'''[[Introduction]]'''

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[[Image: Rapamycin_ball&stickstrt_eyk06.pnf]]

Rapamycin, also known as Sirolimus, is a peptide that was isolated in 1975 from the bacteria strain Streptomyces hygroscopicus found in a soil sample on Easter Island. It is a macrolide, hence accounting for the "-mycin" in its name.

[[Image: streptomyces-hygroscopicus.jpg]]

Rapamycin has been discovered to behave interestingly, possessing a novel mechanism of immunosuppression. Its mode of action differs largely from the other immunosupressants available, bearing great promise for its potential uses and advantages over other treatments.It is currently used as a new immunosuppressant drug, adminstered to precent rejection during organ transplants, particularly kidney transplants. It received approval from the FDA in September 1999, and has since been marketed as an immunosuppresant under the tradename 'Rapamune' by Wyeth-Ayerest.

[[Image: Rapamycin_tradename_eyk06.gif]]

The general shortage of organs available for transplants spells greater need for adrug that boosts the chance of organ survival. Conventional treatments used, such as cyclosporin and FK506, are effective in ensuring the short-term survival of the transplant, but fail in ensuring the organ is accepted by the body in the long run. Rapamycin is hence very important in the treatment of organ transplant patients as it appears to have a different mechanism of action to cyclosporin and FK506, as discussed earlier. In addition,it results in fewer side effects than the standard anti-rejection treatments due to its novel mode of action. Finally, the cytotoxic properties of Rapamycin could also make it effective in the treatment of cancer as Rapamycin is antiproliferative in nature, and there is ongoing research in this field of medicine.

{{Drug-Box |
| Box_Name = Properties of Rapamycin
| ImageFile = [[Image: Rapamycin_chemstrt_eyk06_self.gif]]
| IUPACName = (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
| OtherName = Rapamune, Sirolimus
| CAS_No = 23123-88-9
| ATC_Code = L04AA10
| PubChem = 6436030
| Belstein Registry No. = 604010
| SMILES = O[C@@H]1CC[C@@H](C[C@@H](C)[C@H](CC([C@H](C)/C=C([C@H]
([C@H](C([C@@H]C[C@H](C)/C=C/C=C/C=C(C)/[C@@H](OC)C[C@@H]2CC[C@@H]
(C)[C@@](C(C(N4[C@H]3CCCC4)=O)=O)(O)O2)C)=O)OC)O)\C)=O)O[C@@]3=O)
C[C@H]1OC
| Formula = C54H79NO13
| MolarMass = 914.172 g/mol
| Bioavailability = 20%, decreases after consumption of food rich in fat
| Protein_binding = 92%
| Metabolism = Hepatic
| Half_life = 57 - 63 hours
| Excretion = Mostly faecal
| Liscence data = EU / US
| Pregnancy_cat = C(AU) C(US)
| Legal_status = Rr only (US)
| Routes = Oral
}}

'''[[Other Properties]]'''

'''Optical Rotary Power'''

'''Type''': Alpha

'''Optical Rotary Power''': -58.2 degrees

'''Wavelength''': 589 nm

'''Temperature''': 298.15 K

'''Appearance'''

Off-white to slight yellow powder

'''Purity'''

At least 97% by TLC, HPLC

'''Melting point'''

178°C-182°C

'''Solubility'''

Rapamycin (Sirolimus) gives clear colorless solution at 50mg/ml DMSO

'''Storage'''

-20°C. Protect from light and moisture. Hygroscopic

'''[[Synthesis]]'''

Numerous total synthese of Rapamycin have been reported, on top of many part- and fragments- syntheses.

Rapamycin is a complex molecule, containing a 31-membered ring which includes a pipecolinyl group and pyranose ring, a conjugated triene system and a tri-carbonyl region. It also has 15 chiral centres, suggesting that the number of possible stereoisomers is enormous. The synthesis of Rapamycin hence poses a great challenge to synthetic chemists.

In the following synthesis, published in three separate papers, two fragments of C10-C21 and C22-C42 are formed separately, before being combined to give the total synthesis of rapamycin. Only the main outline of the synthesis will be illustrated on this page as it is too long and complex to show in great detail.

'''''Retro-synthesis'''''

In the retro-synthesis shown below, the molecule is disconnected at the ester group next to '''Carbon 1'''and the '''C21 - C22''' double bond of the triene, producing the synthetic precursors '''2''' and '''3'''. Further disconnections of '''3''' will be shown later. The '''C10-C21''' fragment is first synthesised.

[[Image: Rapamycin_retrosynthesis_eyk06.gif]]

'''''1. Synthesis of C10-C21 fragment'''''

The starting material of synthesis is (R)-methyl 3-hydroxy-2-methylpropionate '''''(8)'''''.

[[Image: Rapamycin_syn_1.gif]]

The starting material '''''(8)''''' is then converted to an alcohol in a '''four-step process'''.

1. Protection of the alcohol as aTHP ether, followed by

2. Reduction,

3. Ether formation and finally,

4. Deprotection steps.

Bromide '''''(9)''''' is formed with the substitution of the hydroxyl group in the product with a bromine. Subsequent reaction of '''''(9)''''' with methyl acetoacetate produced an ester, '''''(10) '''''.

[[Image: Rapamycin_syn_2.gif]]

Catalytic reduction of '''''(10)''''' under Noyori conditions yielded ester '''''(11)''''', which is later converted to its Weinreb amide '''''(12)'''''. Overall, percentage yield of compound '''''(12)''''' is 54%, from a relatively cheap starting material. Vinyl bromide, '''''(13)''''' was then metallated with t-BuLi and the resulting vinyllithium was then combined with '''''(12)''''' and the PMB-protecting group removed to produce '''''(14)'''''. The remaining carbonyl group in '''''(14) ''''' was selectively reduced to a hydroxyl group. In order to differentiate the 1,3-diol, a lactol was formed, where one hydroxyl group ended up in the ring. An oxidation was performed using RuCl2(PPh3)3 to form a lactol. The two remaining alcohol groups can then be methylated using MeI to give '''''(15)'''''.

[[Image: Rapamycin_syn_3.gif]]

The lactol ring opening was achieved using TiCl4 and thiol HS(CH2)2SH to form a dithiolane. The freed alcohol was then protected as its TBS ether and the same protecting group selectively removed from the primary alcohol to form '''''(16)'''''. To avoid removing the dithiolane group at a later stage in the synthesis, the thio-acetal was converted to the dimethyl acetal '''''(17)''''' using PhI(OCOCF3)2 and methanol.

[[Image: Rapamycin_syn_4.gif]]

The next stage in the synthesis was to extend '''''(17)''''' for the building of the triene region. The terminal alcohol was oxidised to its aldehyde using BaMnO4 , then a Wittig reaction was carried out using Ph3P=CHCO2Et and CH2Cl2 to form the second double bond. Reduction of the ester group to an alcohol was carried out using DIBAL-H, then treatment with PPh3. Susequent exposure to the air gave '''Rapamycin fragment 2'''.

'''''2. Synthesis of C22-C42 fragment'''''

Retrosynthesis of '''''(3)'''''gives the three synthetic '''''precursors 5, 6 and 7'''''.
It was thought '''''(4)''''' could be obtained by alkylative coupling of a vinyllithium species generated from '''''(7)''''' to the Weinreb amide '''''(6)'''''. The nucleophilic opening of epoxide '''''(5)''''' by the lithiated sulfone from phenyl sulfone ''(4)'' would then give the desired fragment.

[[Image: Rapamycin_syn_5.gif]]

The ester '''''(18)''''' was used as a starting material to make fragment '''''(6)'''''.

[[Image: Rapamycin_syn_6.gif]]

A Wittig reaction, followed by reduction and protection steps, give '''''(19)'''''. This was hydrogenated using a rhodium catalyst to give syn-dimethyl product '''''(20)'''''. The minor anti diastereomer was successfully separated off. '''''(20)''''' was oxidised, before undergoing an aldol condensation to give adduct '''''(21)'''''.

[[Image: Rapamycin_syn_7.gif]]

Transamination of '''''(21)'''''and protection of the alcohol with PMB produced amide '''''(6) text''''', corresponding to the C22-C28 segment of Rapamycin.

The vinyl bromide '''''(7)''''' was prepared using ester '''''(22)''''' as a starting material.

[[Image: Rapamycin_syn_8.gif]]

Reduction of '''''(22)''''', followed by dibromoolefination, led to product '''''(23)'''''. Acetylene '''''(24)''''' was prepared using n-BuLi, THF and MeI, then sulfenylation with Ph2S2 and bromination gave fragment '''''(7)'''''.

[[Image: Rapamycin_syn_9.gif]]

Iodination and alkylation of starting material '''''(25)''''' with the lithiated allylic sulfide shown followed by a number of further steps, resulted in its conversion to fragment '''''(5)'''''.

[[Image: Rapamycin_syn_10.gif]]

Fragments '''''(7)''''' was first converted to its vinyllithium using t-BuLi, then combined with '''''(6)''''' to form an enone of 78% yield. Stereoselective reduction of the carbonyl group using Zn(BH4)2 gave an alcohol which was protected with DEIPS giving '''''(28)'''''. The phenyl sulfide was oxidised to a sulfone using m-CPBA in excess pyridine.

[[Image: Rapamycin_syn_11.gif]]

Lithiation and addition of the epoxide '''''(50''''' resulted in the hydroxy sulfone in a 4:1 ratio of two diastereomers, which were separated by HPLC. Metalation using n-BuLi followed by oxidation formed the total C22-C42 fragment.

'''''3. Total Synthesis of Rapamycin using combination of C10-C21 and C22-C42 fragments '''''

Fragment '''''(3)''''' (C22-C42) was treated with (S)-Boc-pipecolinal, followed by a Swern oxidation, yielded the aldehyde '''''(29)'''''.

[[Image: Rapamycin_syn_12.gif]]

Condensation with the lithium salt of phosphine oxide 2 (C10-C21) produced the triene as shown below.

[[Image: Rapamycin_syn_13.gif]]

The triene was hydrolysed with pyridinium p-toluenesulfonic acid and an aldol reaction was performed. Treatment with triethylsilyl triflate produced an amino acid, which was subjected to Mukaiyama macrocyclization conditions to form the 31-membered ring.

Finally, deprotection steps were performed to give synthetic Rapamyin '''''(1)'''''. The identity of this Rapamycin sample is confirmed by comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.

'''[[Biological Mechanism]]'''

Rapamycin is believed to block the immune response by causing programmed cell death, otherwise known as apoptosis, in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle.

The diagram below illustrates the complex binding, where FKBP-12 is represented by the blue protein and FRAP the red protein, with Rapamycin between them.

[[Image: Rapamycin_biomech_eyk06.gif]]

This Rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1 of the cell cycle. Rapamycin hence stops the cell at the G1-S transition. As such, the proliferation of T-cells is stopped and apoptosis is induced instead.

Activation of T cells produce a small population of regulatory T cells, which possess the abilibty to control the other T cells that cause rejection. The apoptic death of the many rejection-causing T cells enables the regulatory T cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells though it does not block apoptosis.Therefore, by inducing apoptosis in rejection-causing T cells, Rapamycin can reduce the tendency to reject the transplant, yet allowing the body to develop a tolerance for it.

'''[[Cancer]]'''

Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. Usually, cancer is caused by a p53 mutation, where abnormal cells are prevented from dying by apoptosis. Instead they will continue to divide uncontrollably, reproducing and magnifying the error. Rapamycin could cease the division of cancer cells in a similar fashion in which it stops cell division in T-cells, and also cause apoptosis. It could hence be adminstered in the treatment of cancer.

Studies have revealed that Rapamycin is capable of inhibiting growth and induce cell death by apoptosis in B lymphoma cells.

'''[[References]]'''

http://www.ch.ic.ac.uk/local/projects/russell/index.html

http://en.wikipedia.org/wiki/Sirolimus

Levothyroxine

2007-12-03T12:38:29Z

Eyk06: synthesis of levothyroxine

File:Synthesis levothyroxine.gif

2007-12-03T12:37:11Z

Eyk06: synthesis pathway

synthesis pathway

Levothyroxine

2007-12-03T12:06:51Z

Eyk06: references used

File:Levothyroxine v2 eyk06.gif

2007-12-03T12:04:06Z

Eyk06: clearer version

clearer version

Levothyroxine

2007-12-03T12:00:50Z

Eyk06: hypothyroidism and hyerpthyroidism conditions - brief intro

File:Thyroid gland.gif

2007-12-03T12:00:04Z

Eyk06: thyroid gland location in the human body

thyroid gland location in the human body

Levothyroxine

2007-12-03T11:46:24Z

Eyk06: precautions and side effects

Levothyroxine

2007-12-03T11:38:34Z

Eyk06: rotating structure of Levothyroxine

File:3951.pdb

2007-12-03T11:33:16Z

Eyk06: Rotating image of Levothyroxine

Rotating image of Levothyroxine

Levothyroxine

2007-12-03T11:32:46Z

Eyk06: rotating image of levothyroxine

Levothyroxine

2007-12-03T11:30:16Z

Eyk06: SMILES of Levothyroxine

File:Levothyroxine eyk06.gif

2007-12-03T11:28:50Z

Eyk06: Chemical structure of Levothyroxine

Chemical structure of Levothyroxine

Levothyroxine

2007-12-03T11:28:32Z

Eyk06:

Levothyroxine

2007-12-03T11:21:53Z

Eyk06: Properties of Levothyroxine

Levothyroxine

2007-12-03T11:15:01Z

Eyk06:

Levothyroxine

2007-12-03T11:14:46Z

Eyk06:

'''[[Introduction]]'''

Levothyroxine, otherwise known as L-thyroxine, synthetic T4 or 3,5,3',5'-tetraiodo-L-thyronine, is a synthetic form of thyroxine, which is the key hormone secreted by the follicular cells of the thyroid gland. Both the naturally occuring hormone of T4 and the synthetic form exists in the L-form.

Other common brand names include ""Thyrax"", "Euthyrox", "Levaxin" and "Eltroxin" in Europe, as well as "Levoxyl" and "Synthroid" in the U.S.

'''[[Uses]]'''

Levothyroxine is used to treat hypothyroidism, a condition where the thyroid gland fails to produce sufficient thyroid hormone.
A body deficient in thyroid hormone cannot function properly, resulting in poor growth, slow speech, lack of energy, weight gain, hair loss, dry thick skin, and increased sensitivity to cold. When taken correctly, levothyroxine alleviates these symptoms. In addition, Levothyroxine is adminstered to treat congenital hypothyroidism (cretinism) and goiter (enlarged thyroid gland).

Levothyroxine

2007-12-03T11:14:36Z

Eyk06: Introduction of Levothyroxine and its uses

'''[[Introduction]]'''

Levothyroxine, otherwise known as L-thyroxine, synthetic T4 or 3,5,3',5'-tetraiodo-L-thyronine, is a synthetic form of thyroxine, which is the key hormone secreted by the follicular cells of the thyroid gland. Both the naturally occuring hormone of T4 and the synthetic form exists in the L-form.

Other common brand names include ""Thyrax"", "Euthyrox", "Levaxin" and "Eltroxin" in Europe, as well as "Levoxyl" and "Synthroid" in the U.S.

'''[[Uses]]'''
Levothyroxine is used to treat hypothyroidism, a condition where the thyroid gland fails to produce sufficient thyroid hormone.
A body deficient in thyroid hormone cannot function properly, resulting in poor growth, slow speech, lack of energy, weight gain, hair loss, dry thick skin, and increased sensitivity to cold. When taken correctly, levothyroxine alleviates these symptoms. In addition, Levothyroxine is adminstered to treat congenital hypothyroidism (cretinism) and goiter (enlarged thyroid gland).

It:projects

2007-12-03T11:07:54Z

Eyk06: /* Supplemental Project Page */

__FORCETOC__

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|NEW: This demonstrates the use of Jmol loading discrete molecule files (rather than having to paste them into the wiki page). Upload the molecule file, and invoke it as shown here. Use it for eg loading large proteins etc.--[[User:Rzepa|Rzepa]] 16:07, 4 December 2006 (UTC) and --[[User:Rzepa|Rzepa]] 07:41, 16 October 2007 (BST) and --[[User:Rzepa|Rzepa]] 15:56, 18 October 2007 (BST)

If no rotatable molecule appears to the right there my be a problem in the browser cache - reload the page bypassing the cache using ctrl+F5. If this doesn't work check that [http://www.java.com/en/download/help/testvm.xml Java] is correctly functioning on your system.

===References ===
This shows how citations<ref>Example of adding a citation {{DOI|10.1021/ja9825332}}</ref> can be added to
text<ref>adding a further citation {{DOI|10.1021/ja9825332}}</ref> to produce a nice effect.

===Multiple uses of the same footnote ===

The code for citing multiple quotes from the same source can be found [http://www.mediawiki.org/wiki/Extension:Cite/Cite.php here]. This stops the same reference being stated multiple times at the bottom of the page when you try to reference more than one item from the same source.

=== Collected citations appear below here ===
<references />--[[User:Rzepa|Rzepa]] 15:18, 25 October 2007 (BST)
|<jmol>
<jmolApplet>
<title>Pentahelicene</title><color>yellow</color><size>200</size>
<script>zoom 80; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script>
<uploadedFileContents>Pentahelicene.mol</uploadedFileContents>
</jmolApplet>
<jmolMenu>
<item><text>Start spinning</text><script>spin on</script></item>
<item><text>Stop spinning</text><script>spin off</script></item>
<menuHeight>-1</menuHeight>
</jmolMenu>
<jmolButton>
<script>console</script>
<text>open a console window</text>
</jmolButton>
</jmol>
<jmol><jmolAppletButton><title>Show CIYSIM.cif in popup window</title><color>cyan</color>
<uploadedFileContents>CIYSIM.cif</uploadedFileContents></jmolAppletButton>
</jmol>
|}

== Main Project Page ==

'''''URGENT Announcement'''''

Whilst the Wiki itself is pretty robust, and although it is difficult to break a page on it, this did happen a few days ago to project 12. What seems to have happened is that some ''bad'' code (HTML or XML) was copied from another Web page, and pasted into the project 12 page. The Wiki system could not cope with this particular bad code, and sulked. Fortunately, by invoking appropriate magic, the page has now been restored to its state prior to the breakage, and I have learnt a valuable lesson in how to fix it if this happens again. So this serves as a warning; if you are copying/pasting blind from other web pages (which in general you should not be doing), you do run the risk of breaking the page. Hopefully, the break will be detected during the preview, and serves to remind that you should ''always'' preview before saving to detect any such breaks. --[[User:Rzepa|Rzepa]] 10:21, 28 November 2007 (UTC)

'''Please do not edit this page itself'''. Click on one of the titles to start editing.
{| summary="CIT Project Titles" border="1"
! bgcolor="cyan" |Project<br /> Number
! bgcolor="cyan" |General Keywords
|-
| bgcolor="#CCFF00" |01
| bgcolor="#CCFF00" | [[it07:Lignocaine|Lignocaine (used in dentistry as a "local")]]
|-
| bgcolor="#CCFF00" |02
| bgcolor="#66FF99" | [[it07:Piperine|Piperine (active ingredient of both black and white pepper)]]
|-
| bgcolor="#CCFF00" |03
| bgcolor="#CCFF00" | [[it07:Rapamycin|Rapamycin (prevents transplant rejection)]]
|-
| bgcolor="#CCFF00" |04
| bgcolor="#66FF99" | [[it07:Gossypol|Gossypol (male birth control)]]
|-
| bgcolor="#CCFF00" |05
| bgcolor="#CCFF00" | [[it07:Gentamycin|Gentamicin A (aminoglycoside antibiotic)]]
|-
| bgcolor="#CCFF00" |06
| bgcolor="#66FF99" | [[it07:Herceptin|Herceptin (topical anticancer drug)]]
|-
| bgcolor="#CCFF00" |07
| bgcolor="#CCFF00" | [[it07:Gingerone|Zingerone (the characteristic smell of ginger)]]
|-
| bgcolor="#CCFF00" |08
| bgcolor="#66FF99" | [[it07:Sucralose|Sucralose (non-metabolizable sweetening agent)]]
|-
| bgcolor="#CCFF00" |09
| bgcolor="#CCFF00" | [[it07:Bufotoxin|Bufotoxin (active component of the toad ''Bufo vulgaris'')]]
|-
| bgcolor="#CCFF00" |10
| bgcolor="#66FF99" | [[it07:Roaccutane|Roaccutane (treatment for severe acne)]]
|-
| bgcolor="#CCFF00" |11
| bgcolor="#CCFF00" | [[it07:Sibutramine|Sibutramine (appetite suppresor)]]
|-
| bgcolor="#CCFF00" |12
| bgcolor="#66FF99" | [[it07a:Anandamide|Anandamide (the "feel-good" factor in chocolate)]]
|-
| bgcolor="#CCFF00" |13
| bgcolor="#CCFF00" | [[it07:h3nbh3|Ammonia-borane: H<sub>3</sub>N-BH<sub>3</sub> (Hydrogen storage molecule?)]]
|-
| bgcolor="#CCFF00" |14
| bgcolor="#66FF99" | [[it07:Methoxsalen|Methoxsalen (Treatment of psoriasis)]]
|-
| bgcolor="#CCFF00" |15
| bgcolor="#CCFF00" | [[it07:Hycocine|Hyoscine (From Mandrake and Witches Henbane, pre-med before surgery)]]
|-
| bgcolor="#CCFF00" |16
| bgcolor="#66FF99" | [[it07:Capreomycin|Capreomycin (Drug-resistant TB)]]
|-
| bgcolor="#CCFF00" |17
| bgcolor="#CCFF00" | [[it07:wilkinson|Wilkinson's catalyst]]
|-
| bgcolor="#CCFF00" |18
| bgcolor="#66FF99" | [[it07:Jacobsen|Jacobsen's epoxidation catalyst]]
|-
| bgcolor="#CCFF00" |19
| bgcolor="#CCFF00" | [[it07:Methylaluminoxane|Methylaluminoxane: MAO - hugely important ethylene polymerisation cocatalyst]]
|-
| bgcolor="#CCFF00" |20
| bgcolor="#66FF99" | [[it07:Schwartz|Schwartz reagent for the hydrozirconation of alkenes and alkynes]]
|-
| bgcolor="#CCFF00" |21
| bgcolor="#CCFF00" | [[it07:Schrock|Schrock metathesis catalyst]]
|-
| bgcolor="#CCFF00" |22
| bgcolor="#66FF99" | [[it07:knots|Molecular-scale knots (nanoscale devices)]]
|-
|bgcolor="#CCFF00" |23
| bgcolor="#CCFF00" | [[it07:Vioxx|Vioxx (treatment of osteoarthritis symptoms and pain)]]
|-
| bgcolor="#CCFF00" |24
| bgcolor="#66FF99" | [[it07:Sertraline|Sertraline HCl (anti-depression)]]
|-
| bgcolor="#CCFF00" |25
| bgcolor="#CCFF00" | [[it07:Ceftriaxone|Ceftriaxone (Gonorrhoea)]]
|-
| bgcolor="#CCFF00" |26
| bgcolor="#66FF99" | [[i07t:Zithromycin|Zithromycin (anti-infective)]]
|-
| bgcolor="#CCFF00" |27
| bgcolor="#CCFF00" | [[it07:Lipitor|Lipitor (Cholesterol reducing agent)]]
|-
| bgcolor="#CCFF00" |28
| bgcolor="#66FF99" | [[it07:Cyameluric Acid|Cyameluric acid (Linus Pauling's last idea!)]]
|}

== Supplemental Project Page ==

This area is for people who wish to create their own projects if none of the above appeal to them. Click on the '''Edit''' button to the right to open up an editable page,
then add an entry below as follows

*<nowiki> [[it07:name_of_project|Descriptive name of intended project]]</nowiki>
*This will produce the effect: [[it07:name_of_project|Descriptive name of intended project]]
----
#[[it07:sitagliptin_page|An example entry- in edit mode, please copy this line and paste below to add to this list]]
#[[it07:Limonene|Limonene]]
#[[it07:name_of_project|Vitamin C ]]
#[[it07:Cylcophosphamide|Cyclophosphamide]]
#[[it07:Terbutaline Sulphate|Terbutaline Sulphate]]
#[[it07:Caffeine|Caffeine]]
#[[it07:Mefloquine|Mefloquine]]
#[[it07:Cadaverine|Cadaverine]]
#[[it07:Cyanidin|Cyanidin]]
#[[it07:Ezetimibe|Ezetimibe]]
#[[it07:Octanitrocubane|Octanitrocubane]]
#[[it07:Azadirachtin|Azadirachtin]]
#[[it07:Nicotine|Nicotine]]
#[[it07:Cyclopentasiloxane|Cyclopentasiloxane]]
#[[it07:Trinitrotoluene|Trinitrotoluene]]
#[[it07:Hydroxychloroquine|Hydroxychloroquine]]
#[[it07:Aspartame|Aspartame]]
#[[it07:Azulene|Azulene]]
#[[it07:Chlorine Trifluoride|Chlorine Trifluoride]]
#[[it07:Cholesterol|Cholesterol]]
#[[it07:Vitamin E|Vitamin E]]
#[[it07:Phenothiazine|Phenothiazine]]
#[[it07:linalool|linalool]]
#[[it07:Glutamic acid|Glutamic acid]]
#[[it07:N-(4-hydroxyphenyl)ethanamide|N-(4-hydroxyphenyl)ethanamide]]
#[[it07:Epinephrine|Epinephrine]]
#[[it07:Sodium Valproate|Sodium Valproate]]
#[[it07:Hyaluronic acid |Hyaluronic acid ]]
#[[it07:Methylenedioxymethamphetamine |Methylenedioxymethamphetamine ]]
#[[it07:salicylic acid |salicylic acid ]]
#[[it07:Morphine|Morphine]]
#[[Cetirizine]]
#[[it07:Bisacodyl|Bisacodyl]]
#[[it07:Rivaroxaban|Rivaroxaban]]
#[[it07:Sodium Lauryl Sulfate|Sodium Lauryl Sulfate]]
#[[it07:Silicon Dioxide|Silicon Dioxide]]
#[[it07:Vanillin|Vanillin]]
#[[it07:Tetrahydrocannabinol|Tetrahydrocannabinol]]
#[[it07:Capsaicin|Capsaicin]]
#[[it07:Menthol|Menthol]]
#[[it07:Tamoxifen|Tamoxifen]]
#[[it07:Copper arsenate|Scheele's Green]]
#[[it07:Strychnine|Strychnine]]
#[[it07:Testosterone|Testosterone]]
#[[it07:Monosodium glutamate|Monosodium glutamate]]
#[[it07:Taurine|Taurine]]
#[[it07:Phenethylamine|Phenethylamine]]
#[[it07:Verbenone|Verbenone]]
#[[it07:Salbutamol|Salbutamol]]
#[[it07:Lactic acid|Lactic acid]]
#[[it07:Aspirin|Aspirin]]
#[[it07:EDTA|EDTA]]
#[[it07:Heroin|Heroin]]
#[[it07:Cocaine|Cocaine]]
#[[it07:Myristicin|Myristin (The hallucinogen in nutmeg)]]
#[[it07:Encefabol|Encefabol]]
#[[it07:Sarin|Sarin]]
#[[Thebaine]]
#[[Nitroglycerin]]
#[[it07:Methamphetamine|Methamphetamine]]
#[[it07:Sildenafil|Sildenafil]]
#[[Grubbs' Catalyst]]
#[[it07:Warfarin|Warfarin]]
#[[it07:Angelic Acid|Angelic Acid]]
#[[it07:Melem (Melon)|Melem]]
#[[it07:oxazaborolidines|Chiral Oxazaborolidines as Catalysts]]
#[[it07:RDX|RDX (chemical in plastic explosives)]]
#[[it07:Lysergic Acid|Lysergic Acid]]
#[[it07:Oseltamivir Phosphate|Oseltamivir Phosphate(Tamiflu)]]
#[[Fluoxetine Hydrochloride (Prozac)]]
#[[Dimethylmercury]]
#[[it07:Sorafenib(Nexavar®)|Sorafenib (Nexavar®)]]
#[[Rapamycin]]
#[[Rohypnol]]
#[[it07:Vitamin A|Vitamin A (Retinol)]]
#[[it07:THC|Tetrahydrocannabinol]]
#[[2,4-Dinitrophenylhydrazine|2,4-Dinitrophenylhydrazine]]
#[[Acetylcholine]]
#[[it07:Phenolphthalein|Phenolphthalein]]
#[[Carbon Dioxide]]
#[[Domoic Acid]]
#[[Kevlar]]
#[[it07:Erythromycin|Erythromycin]]
#[[it07:DIBAL|DIBAL]]
#[[Ephedrine]]
#[[it07:Lactose|Lactose]]
#[[it07:Thyjone|Thyjone]]
#[[Levothyroxine]]

== Utilities ==
Utilities have been written to help the conversion of material from HTML.
# [http://diberri.dyndns.org/wikipedia/html2wiki/ A HTML2Wiki Converter]
----

== Wiki Templates ==

[[Template:DOI]] and [[Template:Doi-inline]] are providea as (protected) templates for your use. Many other templates exist, often to be found on e.g. Wikipedia pages. You may decide one of these is of particular use, or of interest. If so, you can install it on the wiki here for you and others to use. Add below a line that looks like Template:Template-name, save, and click on the red text to create the new template. If you prefer the task of adding useful templates to that of adding information about molecules, then you will be given full credit for performing this valuable service for others! --Rzepa 14:41, 20 October 2006 (BST)

[[Template:Chem-Data]]

[[Template:Drug-Box]] - For pharmaceutical drugs just copy variable names and code generates tables

[[Template:Chembox supplement]] - to be linked to from the supplementary section of the table in the template above, for usage see [[Template_talk:chembox_supplement|here]]

[[Template:NFPA_704]] - for notes on how to use, see [[Template_talk:NFPA_704|here]]

[[R & S Phrases]]

[[Template:Chembox new]]

It:projects

2007-12-03T11:04:10Z

Eyk06: /* Supplemental Project Page */

__FORCETOC__

'''''You MUST use the Edit buttons on the right to edit this content. Do NOT use the Edit button on the top of this page.'''''
== Sandbox (Play-Pen) ==

This is an area where you can play without worrying what you do. Enter it by pressing the [Edit] button '''on the right''' and '''not''' at the top. Go here for a [http://en.wikipedia.org/wiki/Wikipedia:Cheatsheet ''cheat sheet''] summary of how to create a Wiki page. It's a free-for-all in here! Learn how to use a Wiki by coming here! PS This is how to do Greek:α, β Δ, δ
Try copying/pasting some of the [http://www.ch.ic.ac.uk/local/it/lab1.html examples in the course work] into this page. See the effect by selecting '''Show Preview'''. Do not use '''Save Page''' so as to leave this area uncluttered for others.
----
{| summary="CIT Project Titles" border="1"
|NEW: This demonstrates the use of Jmol loading discrete molecule files (rather than having to paste them into the wiki page). Upload the molecule file, and invoke it as shown here. Use it for eg loading large proteins etc.--[[User:Rzepa|Rzepa]] 16:07, 4 December 2006 (UTC) and --[[User:Rzepa|Rzepa]] 07:41, 16 October 2007 (BST) and --[[User:Rzepa|Rzepa]] 15:56, 18 October 2007 (BST)

If no rotatable molecule appears to the right there my be a problem in the browser cache - reload the page bypassing the cache using ctrl+F5. If this doesn't work check that [http://www.java.com/en/download/help/testvm.xml Java] is correctly functioning on your system.

===References ===
This shows how citations<ref>Example of adding a citation {{DOI|10.1021/ja9825332}}</ref> can be added to
text<ref>adding a further citation {{DOI|10.1021/ja9825332}}</ref> to produce a nice effect.

===Multiple uses of the same footnote ===

The code for citing multiple quotes from the same source can be found [http://www.mediawiki.org/wiki/Extension:Cite/Cite.php here]. This stops the same reference being stated multiple times at the bottom of the page when you try to reference more than one item from the same source.

=== Collected citations appear below here ===
<references />--[[User:Rzepa|Rzepa]] 15:18, 25 October 2007 (BST)
|<jmol>
<jmolApplet>
<title>Pentahelicene</title><color>yellow</color><size>200</size>
<script>zoom 80; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script>
<uploadedFileContents>Pentahelicene.mol</uploadedFileContents>
</jmolApplet>
<jmolMenu>
<item><text>Start spinning</text><script>spin on</script></item>
<item><text>Stop spinning</text><script>spin off</script></item>
<menuHeight>-1</menuHeight>
</jmolMenu>
<jmolButton>
<script>console</script>
<text>open a console window</text>
</jmolButton>
</jmol>
<jmol><jmolAppletButton><title>Show CIYSIM.cif in popup window</title><color>cyan</color>
<uploadedFileContents>CIYSIM.cif</uploadedFileContents></jmolAppletButton>
</jmol>
|}

== Main Project Page ==

'''''URGENT Announcement'''''

Whilst the Wiki itself is pretty robust, and although it is difficult to break a page on it, this did happen a few days ago to project 12. What seems to have happened is that some ''bad'' code (HTML or XML) was copied from another Web page, and pasted into the project 12 page. The Wiki system could not cope with this particular bad code, and sulked. Fortunately, by invoking appropriate magic, the page has now been restored to its state prior to the breakage, and I have learnt a valuable lesson in how to fix it if this happens again. So this serves as a warning; if you are copying/pasting blind from other web pages (which in general you should not be doing), you do run the risk of breaking the page. Hopefully, the break will be detected during the preview, and serves to remind that you should ''always'' preview before saving to detect any such breaks. --[[User:Rzepa|Rzepa]] 10:21, 28 November 2007 (UTC)

'''Please do not edit this page itself'''. Click on one of the titles to start editing.
{| summary="CIT Project Titles" border="1"
! bgcolor="cyan" |Project<br /> Number
! bgcolor="cyan" |General Keywords
|-
| bgcolor="#CCFF00" |01
| bgcolor="#CCFF00" | [[it07:Lignocaine|Lignocaine (used in dentistry as a "local")]]
|-
| bgcolor="#CCFF00" |02
| bgcolor="#66FF99" | [[it07:Piperine|Piperine (active ingredient of both black and white pepper)]]
|-
| bgcolor="#CCFF00" |03
| bgcolor="#CCFF00" | [[it07:Rapamycin|Rapamycin (prevents transplant rejection)]]
|-
| bgcolor="#CCFF00" |04
| bgcolor="#66FF99" | [[it07:Gossypol|Gossypol (male birth control)]]
|-
| bgcolor="#CCFF00" |05
| bgcolor="#CCFF00" | [[it07:Gentamycin|Gentamicin A (aminoglycoside antibiotic)]]
|-
| bgcolor="#CCFF00" |06
| bgcolor="#66FF99" | [[it07:Herceptin|Herceptin (topical anticancer drug)]]
|-
| bgcolor="#CCFF00" |07
| bgcolor="#CCFF00" | [[it07:Gingerone|Zingerone (the characteristic smell of ginger)]]
|-
| bgcolor="#CCFF00" |08
| bgcolor="#66FF99" | [[it07:Sucralose|Sucralose (non-metabolizable sweetening agent)]]
|-
| bgcolor="#CCFF00" |09
| bgcolor="#CCFF00" | [[it07:Bufotoxin|Bufotoxin (active component of the toad ''Bufo vulgaris'')]]
|-
| bgcolor="#CCFF00" |10
| bgcolor="#66FF99" | [[it07:Roaccutane|Roaccutane (treatment for severe acne)]]
|-
| bgcolor="#CCFF00" |11
| bgcolor="#CCFF00" | [[it07:Sibutramine|Sibutramine (appetite suppresor)]]
|-
| bgcolor="#CCFF00" |12
| bgcolor="#66FF99" | [[it07a:Anandamide|Anandamide (the "feel-good" factor in chocolate)]]
|-
| bgcolor="#CCFF00" |13
| bgcolor="#CCFF00" | [[it07:h3nbh3|Ammonia-borane: H<sub>3</sub>N-BH<sub>3</sub> (Hydrogen storage molecule?)]]
|-
| bgcolor="#CCFF00" |14
| bgcolor="#66FF99" | [[it07:Methoxsalen|Methoxsalen (Treatment of psoriasis)]]
|-
| bgcolor="#CCFF00" |15
| bgcolor="#CCFF00" | [[it07:Hycocine|Hyoscine (From Mandrake and Witches Henbane, pre-med before surgery)]]
|-
| bgcolor="#CCFF00" |16
| bgcolor="#66FF99" | [[it07:Capreomycin|Capreomycin (Drug-resistant TB)]]
|-
| bgcolor="#CCFF00" |17
| bgcolor="#CCFF00" | [[it07:wilkinson|Wilkinson's catalyst]]
|-
| bgcolor="#CCFF00" |18
| bgcolor="#66FF99" | [[it07:Jacobsen|Jacobsen's epoxidation catalyst]]
|-
| bgcolor="#CCFF00" |19
| bgcolor="#CCFF00" | [[it07:Methylaluminoxane|Methylaluminoxane: MAO - hugely important ethylene polymerisation cocatalyst]]
|-
| bgcolor="#CCFF00" |20
| bgcolor="#66FF99" | [[it07:Schwartz|Schwartz reagent for the hydrozirconation of alkenes and alkynes]]
|-
| bgcolor="#CCFF00" |21
| bgcolor="#CCFF00" | [[it07:Schrock|Schrock metathesis catalyst]]
|-
| bgcolor="#CCFF00" |22
| bgcolor="#66FF99" | [[it07:knots|Molecular-scale knots (nanoscale devices)]]
|-
|bgcolor="#CCFF00" |23
| bgcolor="#CCFF00" | [[it07:Vioxx|Vioxx (treatment of osteoarthritis symptoms and pain)]]
|-
| bgcolor="#CCFF00" |24
| bgcolor="#66FF99" | [[it07:Sertraline|Sertraline HCl (anti-depression)]]
|-
| bgcolor="#CCFF00" |25
| bgcolor="#CCFF00" | [[it07:Ceftriaxone|Ceftriaxone (Gonorrhoea)]]
|-
| bgcolor="#CCFF00" |26
| bgcolor="#66FF99" | [[i07t:Zithromycin|Zithromycin (anti-infective)]]
|-
| bgcolor="#CCFF00" |27
| bgcolor="#CCFF00" | [[it07:Lipitor|Lipitor (Cholesterol reducing agent)]]
|-
| bgcolor="#CCFF00" |28
| bgcolor="#66FF99" | [[it07:Cyameluric Acid|Cyameluric acid (Linus Pauling's last idea!)]]
|}

== Supplemental Project Page ==

This area is for people who wish to create their own projects if none of the above appeal to them. Click on the '''Edit''' button to the right to open up an editable page,
then add an entry below as follows

*<nowiki> [[it07:name_of_project|Descriptive name of intended project]]</nowiki>
*This will produce the effect: [[it07:name_of_project|Descriptive name of intended project]]
----
#[[it07:sitagliptin_page|An example entry- in edit mode, please copy this line and paste below to add to this list]]
#[[it07:Limonene|Limonene]]
#[[it07:name_of_project|Vitamin C ]]
#[[it07:Cylcophosphamide|Cyclophosphamide]]
#[[it07:Terbutaline Sulphate|Terbutaline Sulphate]]
#[[it07:Caffeine|Caffeine]]
#[[it07:Mefloquine|Mefloquine]]
#[[it07:Cadaverine|Cadaverine]]
#[[it07:Cyanidin|Cyanidin]]
#[[it07:Ezetimibe|Ezetimibe]]
#[[it07:Octanitrocubane|Octanitrocubane]]
#[[it07:Azadirachtin|Azadirachtin]]
#[[it07:Nicotine|Nicotine]]
#[[it07:Cyclopentasiloxane|Cyclopentasiloxane]]
#[[it07:Trinitrotoluene|Trinitrotoluene]]
#[[it07:Hydroxychloroquine|Hydroxychloroquine]]
#[[it07:Aspartame|Aspartame]]
#[[it07:Azulene|Azulene]]
#[[it07:Chlorine Trifluoride|Chlorine Trifluoride]]
#[[it07:Cholesterol|Cholesterol]]
#[[it07:Vitamin E|Vitamin E]]
#[[it07:Phenothiazine|Phenothiazine]]
#[[it07:linalool|linalool]]
#[[it07:Glutamic acid|Glutamic acid]]
#[[it07:N-(4-hydroxyphenyl)ethanamide|N-(4-hydroxyphenyl)ethanamide]]
#[[it07:Epinephrine|Epinephrine]]
#[[it07:Sodium Valproate|Sodium Valproate]]
#[[it07:Hyaluronic acid |Hyaluronic acid ]]
#[[it07:Methylenedioxymethamphetamine |Methylenedioxymethamphetamine ]]
#[[it07:salicylic acid |salicylic acid ]]
#[[it07:Morphine|Morphine]]
#[[Cetirizine]]
#[[it07:Bisacodyl|Bisacodyl]]
#[[it07:Rivaroxaban|Rivaroxaban]]
#[[it07:Sodium Lauryl Sulfate|Sodium Lauryl Sulfate]]
#[[it07:Silicon Dioxide|Silicon Dioxide]]
#[[it07:Vanillin|Vanillin]]
#[[it07:Tetrahydrocannabinol|Tetrahydrocannabinol]]
#[[it07:Capsaicin|Capsaicin]]
#[[it07:Menthol|Menthol]]
#[[it07:Tamoxifen|Tamoxifen]]
#[[it07:Copper arsenate|Scheele's Green]]
#[[it07:Strychnine|Strychnine]]
#[[it07:Testosterone|Testosterone]]
#[[it07:Monosodium glutamate|Monosodium glutamate]]
#[[it07:Taurine|Taurine]]
#[[it07:Phenethylamine|Phenethylamine]]
#[[it07:Verbenone|Verbenone]]
#[[it07:Salbutamol|Salbutamol]]
#[[it07:Lactic acid|Lactic acid]]
#[[it07:Aspirin|Aspirin]]
#[[it07:EDTA|EDTA]]
#[[it07:Heroin|Heroin]]
#[[it07:Cocaine|Cocaine]]
#[[it07:Myristicin|Myristin (The hallucinogen in nutmeg)]]
#[[it07:Encefabol|Encefabol]]
#[[it07:Sarin|Sarin]]
#[[Thebaine]]
#[[Nitroglycerin]]
#[[it07:Methamphetamine|Methamphetamine]]
#[[it07:Sildenafil|Sildenafil]]
#[[Grubbs' Catalyst]]
#[[it07:Warfarin|Warfarin]]
#[[it07:Angelic Acid|Angelic Acid]]
#[[it07:Melem (Melon)|Melem]]
#[[it07:oxazaborolidines|Chiral Oxazaborolidines as Catalysts]]
#[[it07:RDX|RDX (chemical in plastic explosives)]]
#[[it07:Lysergic Acid|Lysergic Acid]]
#[[it07:Oseltamivir Phosphate|Oseltamivir Phosphate(Tamiflu)]]
#[[Fluoxetine Hydrochloride (Prozac)]]
#[[Dimethylmercury]]
#[[it07:Sorafenib(Nexavar®)|Sorafenib (Nexavar®)]]
#[[Rapamycin]]
#[[Rohypnol]]
#[[it07:Vitamin A|Vitamin A (Retinol)]]
#[[it07:THC|Tetrahydrocannabinol]]
#[[2,4-Dinitrophenylhydrazine|2,4-Dinitrophenylhydrazine]]
#[[Acetylcholine]]
#[[it07:Phenolphthalein|Phenolphthalein]]
#[[Carbon Dioxide]]
#[[Domoic Acid]]
#[[Kevlar]]
#[[it07:Erythromycin|Erythromycin]]
#[[it07:DIBAL|DIBAL]]
#[[Ephedrine]]
#[[it07:Lactose|Lactose]]
#[[it07:Thyjone|Thyjone]]
#[[Thyroxine]]

== Utilities ==
Utilities have been written to help the conversion of material from HTML.
# [http://diberri.dyndns.org/wikipedia/html2wiki/ A HTML2Wiki Converter]
----

== Wiki Templates ==

[[Template:DOI]] and [[Template:Doi-inline]] are providea as (protected) templates for your use. Many other templates exist, often to be found on e.g. Wikipedia pages. You may decide one of these is of particular use, or of interest. If so, you can install it on the wiki here for you and others to use. Add below a line that looks like Template:Template-name, save, and click on the red text to create the new template. If you prefer the task of adding useful templates to that of adding information about molecules, then you will be given full credit for performing this valuable service for others! --Rzepa 14:41, 20 October 2006 (BST)

[[Template:Chem-Data]]

[[Template:Drug-Box]] - For pharmaceutical drugs just copy variable names and code generates tables

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It:projects

2007-12-03T11:03:49Z

Eyk06: /* Supplemental Project Page */

__FORCETOC__

'''''You MUST use the Edit buttons on the right to edit this content. Do NOT use the Edit button on the top of this page.'''''
== Sandbox (Play-Pen) ==

This is an area where you can play without worrying what you do. Enter it by pressing the [Edit] button '''on the right''' and '''not''' at the top. Go here for a [http://en.wikipedia.org/wiki/Wikipedia:Cheatsheet ''cheat sheet''] summary of how to create a Wiki page. It's a free-for-all in here! Learn how to use a Wiki by coming here! PS This is how to do Greek:α, β Δ, δ
Try copying/pasting some of the [http://www.ch.ic.ac.uk/local/it/lab1.html examples in the course work] into this page. See the effect by selecting '''Show Preview'''. Do not use '''Save Page''' so as to leave this area uncluttered for others.
----
{| summary="CIT Project Titles" border="1"
|NEW: This demonstrates the use of Jmol loading discrete molecule files (rather than having to paste them into the wiki page). Upload the molecule file, and invoke it as shown here. Use it for eg loading large proteins etc.--[[User:Rzepa|Rzepa]] 16:07, 4 December 2006 (UTC) and --[[User:Rzepa|Rzepa]] 07:41, 16 October 2007 (BST) and --[[User:Rzepa|Rzepa]] 15:56, 18 October 2007 (BST)

If no rotatable molecule appears to the right there my be a problem in the browser cache - reload the page bypassing the cache using ctrl+F5. If this doesn't work check that [http://www.java.com/en/download/help/testvm.xml Java] is correctly functioning on your system.

===References ===
This shows how citations<ref>Example of adding a citation {{DOI|10.1021/ja9825332}}</ref> can be added to
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=== Collected citations appear below here ===
<references />--[[User:Rzepa|Rzepa]] 15:18, 25 October 2007 (BST)
|<jmol>
<jmolApplet>
<title>Pentahelicene</title><color>yellow</color><size>200</size>
<script>zoom 80; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script>
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== Main Project Page ==

'''''URGENT Announcement'''''

Whilst the Wiki itself is pretty robust, and although it is difficult to break a page on it, this did happen a few days ago to project 12. What seems to have happened is that some ''bad'' code (HTML or XML) was copied from another Web page, and pasted into the project 12 page. The Wiki system could not cope with this particular bad code, and sulked. Fortunately, by invoking appropriate magic, the page has now been restored to its state prior to the breakage, and I have learnt a valuable lesson in how to fix it if this happens again. So this serves as a warning; if you are copying/pasting blind from other web pages (which in general you should not be doing), you do run the risk of breaking the page. Hopefully, the break will be detected during the preview, and serves to remind that you should ''always'' preview before saving to detect any such breaks. --[[User:Rzepa|Rzepa]] 10:21, 28 November 2007 (UTC)

'''Please do not edit this page itself'''. Click on one of the titles to start editing.
{| summary="CIT Project Titles" border="1"
! bgcolor="cyan" |Project<br /> Number
! bgcolor="cyan" |General Keywords
|-
| bgcolor="#CCFF00" |01
| bgcolor="#CCFF00" | [[it07:Lignocaine|Lignocaine (used in dentistry as a "local")]]
|-
| bgcolor="#CCFF00" |02
| bgcolor="#66FF99" | [[it07:Piperine|Piperine (active ingredient of both black and white pepper)]]
|-
| bgcolor="#CCFF00" |03
| bgcolor="#CCFF00" | [[it07:Rapamycin|Rapamycin (prevents transplant rejection)]]
|-
| bgcolor="#CCFF00" |04
| bgcolor="#66FF99" | [[it07:Gossypol|Gossypol (male birth control)]]
|-
| bgcolor="#CCFF00" |05
| bgcolor="#CCFF00" | [[it07:Gentamycin|Gentamicin A (aminoglycoside antibiotic)]]
|-
| bgcolor="#CCFF00" |06
| bgcolor="#66FF99" | [[it07:Herceptin|Herceptin (topical anticancer drug)]]
|-
| bgcolor="#CCFF00" |07
| bgcolor="#CCFF00" | [[it07:Gingerone|Zingerone (the characteristic smell of ginger)]]
|-
| bgcolor="#CCFF00" |08
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|-
| bgcolor="#CCFF00" |09
| bgcolor="#CCFF00" | [[it07:Bufotoxin|Bufotoxin (active component of the toad ''Bufo vulgaris'')]]
|-
| bgcolor="#CCFF00" |10
| bgcolor="#66FF99" | [[it07:Roaccutane|Roaccutane (treatment for severe acne)]]
|-
| bgcolor="#CCFF00" |11
| bgcolor="#CCFF00" | [[it07:Sibutramine|Sibutramine (appetite suppresor)]]
|-
| bgcolor="#CCFF00" |12
| bgcolor="#66FF99" | [[it07a:Anandamide|Anandamide (the "feel-good" factor in chocolate)]]
|-
| bgcolor="#CCFF00" |13
| bgcolor="#CCFF00" | [[it07:h3nbh3|Ammonia-borane: H<sub>3</sub>N-BH<sub>3</sub> (Hydrogen storage molecule?)]]
|-
| bgcolor="#CCFF00" |14
| bgcolor="#66FF99" | [[it07:Methoxsalen|Methoxsalen (Treatment of psoriasis)]]
|-
| bgcolor="#CCFF00" |15
| bgcolor="#CCFF00" | [[it07:Hycocine|Hyoscine (From Mandrake and Witches Henbane, pre-med before surgery)]]
|-
| bgcolor="#CCFF00" |16
| bgcolor="#66FF99" | [[it07:Capreomycin|Capreomycin (Drug-resistant TB)]]
|-
| bgcolor="#CCFF00" |17
| bgcolor="#CCFF00" | [[it07:wilkinson|Wilkinson's catalyst]]
|-
| bgcolor="#CCFF00" |18
| bgcolor="#66FF99" | [[it07:Jacobsen|Jacobsen's epoxidation catalyst]]
|-
| bgcolor="#CCFF00" |19
| bgcolor="#CCFF00" | [[it07:Methylaluminoxane|Methylaluminoxane: MAO - hugely important ethylene polymerisation cocatalyst]]
|-
| bgcolor="#CCFF00" |20
| bgcolor="#66FF99" | [[it07:Schwartz|Schwartz reagent for the hydrozirconation of alkenes and alkynes]]
|-
| bgcolor="#CCFF00" |21
| bgcolor="#CCFF00" | [[it07:Schrock|Schrock metathesis catalyst]]
|-
| bgcolor="#CCFF00" |22
| bgcolor="#66FF99" | [[it07:knots|Molecular-scale knots (nanoscale devices)]]
|-
|bgcolor="#CCFF00" |23
| bgcolor="#CCFF00" | [[it07:Vioxx|Vioxx (treatment of osteoarthritis symptoms and pain)]]
|-
| bgcolor="#CCFF00" |24
| bgcolor="#66FF99" | [[it07:Sertraline|Sertraline HCl (anti-depression)]]
|-
| bgcolor="#CCFF00" |25
| bgcolor="#CCFF00" | [[it07:Ceftriaxone|Ceftriaxone (Gonorrhoea)]]
|-
| bgcolor="#CCFF00" |26
| bgcolor="#66FF99" | [[i07t:Zithromycin|Zithromycin (anti-infective)]]
|-
| bgcolor="#CCFF00" |27
| bgcolor="#CCFF00" | [[it07:Lipitor|Lipitor (Cholesterol reducing agent)]]
|-
| bgcolor="#CCFF00" |28
| bgcolor="#66FF99" | [[it07:Cyameluric Acid|Cyameluric acid (Linus Pauling's last idea!)]]
|}

== Supplemental Project Page ==

This area is for people who wish to create their own projects if none of the above appeal to them. Click on the '''Edit''' button to the right to open up an editable page,
then add an entry below as follows

*<nowiki> [[it07:name_of_project|Descriptive name of intended project]]</nowiki>
*This will produce the effect: [[it07:name_of_project|Descriptive name of intended project]]
----
#[[it07:sitagliptin_page|An example entry- in edit mode, please copy this line and paste below to add to this list]]
#[[it07:Limonene|Limonene]]
#[[it07:name_of_project|Vitamin C ]]
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#[[it07:oxazaborolidines|Chiral Oxazaborolidines as Catalysts]]
#[[it07:RDX|RDX (chemical in plastic explosives)]]
#[[it07:Lysergic Acid|Lysergic Acid]]
#[[it07:Oseltamivir Phosphate|Oseltamivir Phosphate(Tamiflu)]]
#[[Fluoxetine Hydrochloride (Prozac)]]
#[[Dimethylmercury]]
#[[it07:Sorafenib(Nexavar®)|Sorafenib (Nexavar®)]]
#[[Rapamycin]]
#[[Rohypnol]]
#[[it07:Vitamin A|Vitamin A (Retinol)]]
#[[it07:THC|Tetrahydrocannabinol]]
#[[2,4-Dinitrophenylhydrazine|2,4-Dinitrophenylhydrazine]]
#[[Acetylcholine]]
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#[[Carbon Dioxide]]
#[[Domoic Acid]]
#[[Kevlar]]
#[[it07:Erythromycin|Erythromycin]]
#[[it07:DIBAL|DIBAL]]
#[[Ephedrine]]
#[[it07:Lactose|Lactose]]
#[[it07:Thyjone|Thyjone]]
#[[it07:Thyroxine]]

== Utilities ==
Utilities have been written to help the conversion of material from HTML.
# [http://diberri.dyndns.org/wikipedia/html2wiki/ A HTML2Wiki Converter]
----

== Wiki Templates ==

[[Template:DOI]] and [[Template:Doi-inline]] are providea as (protected) templates for your use. Many other templates exist, often to be found on e.g. Wikipedia pages. You may decide one of these is of particular use, or of interest. If so, you can install it on the wiki here for you and others to use. Add below a line that looks like Template:Template-name, save, and click on the red text to create the new template. If you prefer the task of adding useful templates to that of adding information about molecules, then you will be given full credit for performing this valuable service for others! --Rzepa 14:41, 20 October 2006 (BST)

[[Template:Chem-Data]]

[[Template:Drug-Box]] - For pharmaceutical drugs just copy variable names and code generates tables

[[Template:Chembox supplement]] - to be linked to from the supplementary section of the table in the template above, for usage see [[Template_talk:chembox_supplement|here]]

[[Template:NFPA_704]] - for notes on how to use, see [[Template_talk:NFPA_704|here]]

[[R & S Phrases]]

[[Template:Chembox new]]

Rapamycin

2007-12-03T10:45:12Z

Eyk06: picture of streptomyces hygroscopicus and more properties

'''[[Introduction]]'''

|<jmol>
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<text>open a console window</text>
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<jmol><jmolAppletButton><title>Show CIYSIM.cif in popup window</title><color>cyan</color>
<uploadedFileContents>CIYSIM.cif</uploadedFileContents></jmolAppletButton>
</jmol>

[[Image: Rapamycin_ball&stickstrt_eyk06.pnf]]

Rapamycin, also known as Sirolimus, is a peptide that was isolated in 1975 from the bacteria strain Streptomyces hygroscopicus found in a soil sample on Easter Island. It is a macrolide, hence accounting for the "-mycin" in its name.

[[Image: streptomyces-hygroscopicus.jpg]]

Rapamycin has been discovered to behave interestingly, possessing a novel mechanism of immunosuppression. Its mode of action differs largely from the other immunosupressants available, bearing great promise for its potential uses and advantages over other treatments.It is currently used as a new immunosuppressant drug, adminstered to precent rejection during organ transplants, particularly kidney transplants. It received approval from the FDA in September 1999, and has since been marketed as an immunosuppresant under the tradename 'Rapamune' by Wyeth-Ayerest.

[[Image: Rapamycin_tradename_eyk06.gif]]

The general shortage of organs available for transplants spells greater need for adrug that boosts the chance of organ survival. Conventional treatments used, such as cyclosporin and FK506, are effective in ensuring the short-term survival of the transplant, but fail in ensuring the organ is accepted by the body in the long run. Rapamycin is hence very important in the treatment of organ transplant patients as it appears to have a different mechanism of action to cyclosporin and FK506, as discussed earlier. In addition,it results in fewer side effects than the standard anti-rejection treatments due to its novel mode of action. Finally, the cytotoxic properties of Rapamycin could also make it effective in the treatment of cancer as Rapamycin is antiproliferative in nature, and there is ongoing research in this field of medicine.

{{Drug-Box |
| Box_Name = Properties of Rapamycin
| ImageFile = [[Image: Rapamycin_chemstrt_eyk06_self.gif]]
| IUPACName = (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
| OtherName = Rapamune, Sirolimus
| CAS_No = 23123-88-9
| ATC_Code = L04AA10
| PubChem = 6436030
| Belstein Registry No. = 604010
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = C54H79NO13
| MolarMass = 914.172 g/mol
| Bioavailability = 20%, decreases after consumption of food rich in fat
| Protein_binding = 92%
| Metabolism = Hepatic
| Half_life = 57 - 63 hours
| Excretion = Mostly faecal
| Liscence data = EU / US
| Pregnancy_cat = C(AU) C(US)
| Legal_status = Rr only (US)
| Routes = Oral
}}

'''[[Other Properties]]'''

'''Optical Rotary Power'''

'''Type''': Alpha

'''Optical Rotary Power''': -58.2 degrees

'''Wavelength''': 589 nm

'''Temperature''': 298.15 K

'''Appearance'''

Off-white to slight yellow powder

'''Purity'''

At least 97% by TLC, HPLC

'''Melting point'''

178°C-182°C

'''Solubility'''

Rapamycin (Sirolimus) gives clear colorless solution at 50mg/ml DMSO

'''Storage'''

-20°C. Protect from light and moisture. Hygroscopic

'''[[Synthesis]]'''

Numerous total synthese of Rapamycin have been reported, on top of many part- and fragments- syntheses.

Rapamycin is a complex molecule, containing a 31-membered ring which includes a pipecolinyl group and pyranose ring, a conjugated triene system and a tri-carbonyl region. It also has 15 chiral centres, suggesting that the number of possible stereoisomers is enormous. The synthesis of Rapamycin hence poses a great challenge to synthetic chemists.

In the following synthesis, published in three separate papers, two fragments of C10-C21 and C22-C42 are formed separately, before being combined to give the total synthesis of rapamycin. Only the main outline of the synthesis will be illustrated on this page as it is too long and complex to show in great detail.

'''''Retro-synthesis'''''

In the retro-synthesis shown below, the molecule is disconnected at the ester group next to '''Carbon 1'''and the '''C21 - C22''' double bond of the triene, producing the synthetic precursors '''2''' and '''3'''. Further disconnections of '''3''' will be shown later. The '''C10-C21''' fragment is first synthesised.

[[Image: Rapamycin_retrosynthesis_eyk06.gif]]

'''''1. Synthesis of C10-C21 fragment'''''

The starting material of synthesis is (R)-methyl 3-hydroxy-2-methylpropionate '''''(8)'''''.

[[Image: Rapamycin_syn_1.gif]]

The starting material '''''(8)''''' is then converted to an alcohol in a '''four-step process'''.

1. Protection of the alcohol as aTHP ether, followed by

2. Reduction,

3. Ether formation and finally,

4. Deprotection steps.

Bromide '''''(9)''''' is formed with the substitution of the hydroxyl group in the product with a bromine. Subsequent reaction of '''''(9)''''' with methyl acetoacetate produced an ester, '''''(10) '''''.

[[Image: Rapamycin_syn_2.gif]]

Catalytic reduction of '''''(10)''''' under Noyori conditions yielded ester '''''(11)''''', which is later converted to its Weinreb amide '''''(12)'''''. Overall, percentage yield of compound '''''(12)''''' is 54%, from a relatively cheap starting material. Vinyl bromide, '''''(13)''''' was then metallated with t-BuLi and the resulting vinyllithium was then combined with '''''(12)''''' and the PMB-protecting group removed to produce '''''(14)'''''. The remaining carbonyl group in '''''(14) ''''' was selectively reduced to a hydroxyl group. In order to differentiate the 1,3-diol, a lactol was formed, where one hydroxyl group ended up in the ring. An oxidation was performed using RuCl2(PPh3)3 to form a lactol. The two remaining alcohol groups can then be methylated using MeI to give '''''(15)'''''.

[[Image: Rapamycin_syn_3.gif]]

The lactol ring opening was achieved using TiCl4 and thiol HS(CH2)2SH to form a dithiolane. The freed alcohol was then protected as its TBS ether and the same protecting group selectively removed from the primary alcohol to form '''''(16)'''''. To avoid removing the dithiolane group at a later stage in the synthesis, the thio-acetal was converted to the dimethyl acetal '''''(17)''''' using PhI(OCOCF3)2 and methanol.

[[Image: Rapamycin_syn_4.gif]]

The next stage in the synthesis was to extend '''''(17)''''' for the building of the triene region. The terminal alcohol was oxidised to its aldehyde using BaMnO4 , then a Wittig reaction was carried out using Ph3P=CHCO2Et and CH2Cl2 to form the second double bond. Reduction of the ester group to an alcohol was carried out using DIBAL-H, then treatment with PPh3. Susequent exposure to the air gave '''Rapamycin fragment 2'''.

'''''2. Synthesis of C22-C42 fragment'''''

Retrosynthesis of '''''(3)'''''gives the three synthetic '''''precursors 5, 6 and 7'''''.
It was thought '''''(4)''''' could be obtained by alkylative coupling of a vinyllithium species generated from '''''(7)''''' to the Weinreb amide '''''(6)'''''. The nucleophilic opening of epoxide '''''(5)''''' by the lithiated sulfone from phenyl sulfone ''(4)'' would then give the desired fragment.

[[Image: Rapamycin_syn_5.gif]]

The ester '''''(18)''''' was used as a starting material to make fragment '''''(6)'''''.

[[Image: Rapamycin_syn_6.gif]]

A Wittig reaction, followed by reduction and protection steps, give '''''(19)'''''. This was hydrogenated using a rhodium catalyst to give syn-dimethyl product '''''(20)'''''. The minor anti diastereomer was successfully separated off. '''''(20)''''' was oxidised, before undergoing an aldol condensation to give adduct '''''(21)'''''.

[[Image: Rapamycin_syn_7.gif]]

Transamination of '''''(21)'''''and protection of the alcohol with PMB produced amide '''''(6) text''''', corresponding to the C22-C28 segment of Rapamycin.

The vinyl bromide '''''(7)''''' was prepared using ester '''''(22)''''' as a starting material.

[[Image: Rapamycin_syn_8.gif]]

Reduction of '''''(22)''''', followed by dibromoolefination, led to product '''''(23)'''''. Acetylene '''''(24)''''' was prepared using n-BuLi, THF and MeI, then sulfenylation with Ph2S2 and bromination gave fragment '''''(7)'''''.

[[Image: Rapamycin_syn_9.gif]]

Iodination and alkylation of starting material '''''(25)''''' with the lithiated allylic sulfide shown followed by a number of further steps, resulted in its conversion to fragment '''''(5)'''''.

[[Image: Rapamycin_syn_10.gif]]

Fragments '''''(7)''''' was first converted to its vinyllithium using t-BuLi, then combined with '''''(6)''''' to form an enone of 78% yield. Stereoselective reduction of the carbonyl group using Zn(BH4)2 gave an alcohol which was protected with DEIPS giving '''''(28)'''''. The phenyl sulfide was oxidised to a sulfone using m-CPBA in excess pyridine.

[[Image: Rapamycin_syn_11.gif]]

Lithiation and addition of the epoxide '''''(50''''' resulted in the hydroxy sulfone in a 4:1 ratio of two diastereomers, which were separated by HPLC. Metalation using n-BuLi followed by oxidation formed the total C22-C42 fragment.

'''''3. Total Synthesis of Rapamycin using combination of C10-C21 and C22-C42 fragments '''''

Fragment '''''(3)''''' (C22-C42) was treated with (S)-Boc-pipecolinal, followed by a Swern oxidation, yielded the aldehyde '''''(29)'''''.

[[Image: Rapamycin_syn_12.gif]]

Condensation with the lithium salt of phosphine oxide 2 (C10-C21) produced the triene as shown below.

[[Image: Rapamycin_syn_13.gif]]

The triene was hydrolysed with pyridinium p-toluenesulfonic acid and an aldol reaction was performed. Treatment with triethylsilyl triflate produced an amino acid, which was subjected to Mukaiyama macrocyclization conditions to form the 31-membered ring.

Finally, deprotection steps were performed to give synthetic Rapamyin '''''(1)'''''. The identity of this Rapamycin sample is confirmed by comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.

'''[[Biological Mechanism]]'''

Rapamycin is believed to block the immune response by causing programmed cell death, otherwise known as apoptosis, in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle.

The diagram below illustrates the complex binding, where FKBP-12 is represented by the blue protein and FRAP the red protein, with Rapamycin between them.

[[Image: Rapamycin_biomech_eyk06.gif]]

This Rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1 of the cell cycle. Rapamycin hence stops the cell at the G1-S transition. As such, the proliferation of T-cells is stopped and apoptosis is induced instead.

Activation of T cells produce a small population of regulatory T cells, which possess the abilibty to control the other T cells that cause rejection. The apoptic death of the many rejection-causing T cells enables the regulatory T cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells though it does not block apoptosis.Therefore, by inducing apoptosis in rejection-causing T cells, Rapamycin can reduce the tendency to reject the transplant, yet allowing the body to develop a tolerance for it.

'''[[Cancer]]'''

Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. Usually, cancer is caused by a p53 mutation, where abnormal cells are prevented from dying by apoptosis. Instead they will continue to divide uncontrollably, reproducing and magnifying the error. Rapamycin could cease the division of cancer cells in a similar fashion in which it stops cell division in T-cells, and also cause apoptosis. It could hence be adminstered in the treatment of cancer.

Studies have revealed that Rapamycin is capable of inhibiting growth and induce cell death by apoptosis in B lymphoma cells.

'''[[References]]'''

http://www.ch.ic.ac.uk/local/projects/russell/index.html

http://en.wikipedia.org/wiki/Sirolimus

File:Streptomyces-hygroscopicus.jpg

2007-12-03T10:39:15Z

Eyk06: picture of Streptomyces-hygroscopicus

picture of Streptomyces-hygroscopicus

Rapamycin

2007-11-27T14:53:09Z

Eyk06: references used

'''[[Introduction]]'''

|<jmol>
<jmolApplet>
<title>Cyclopentasiloxane</title><color>black</color><size>400</size>
<script>zoom 90; cpk -25;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script>
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<uploadedFileContents>CIYSIM.cif</uploadedFileContents></jmolAppletButton>
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[[Image: Rapamycin_ball&stickstrt_eyk06.pnf]]

Rapamycin, also known as Sirolimus, is a peptide that was isolated in 1975 from the bacteria strain Streptomyces hygroscopicus found in a soil sample on Easter Island. It is a macrolide, hence accounting for the "-mycin" in its name.

Rapamycin has been discovered to behave interestingly, possessing a novel mechanism of immunosuppression. Its mode of action differs largely from the other immunosupressants available, bearing great promise for its potential uses and advantages over other treatments.It is currently used as a new immunosuppressant drug, adminstered to precent rejection during organ transplants, particularly kidney transplants. It received approval from the FDA in September 1999, and has since been marketed as an immunosuppresant under the tradename 'Rapamune' by Wyeth-Ayerest.

[[Image: Rapamycin_tradename_eyk06.gif]]

The general shortage of organs available for transplants spells greater need for adrug that boosts the chance of organ survival. Conventional treatments used, such as cyclosporin and FK506, are effective in ensuring the short-term survival of the transplant, but fail in ensuring the organ is accepted by the body in the long run. Rapamycin is hence very important in the treatment of organ transplant patients as it appears to have a different mechanism of action to cyclosporin and FK506, as discussed earlier. In addition,it results in fewer side effects than the standard anti-rejection treatments due to its novel mode of action. Finally, the cytotoxic properties of Rapamycin could also make it effective in the treatment of cancer as Rapamycin is antiproliferative in nature, and there is ongoing research in this field of medicine.

{{Drug-Box |
| Box_Name = Properties of Rapamycin
| ImageFile = [[Image: Rapamycin_chemstrt_eyk06_self.gif]]
| IUPACName = (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
| OtherName = Rapamune, Sirolimus
| CAS_No = 23123-88-9
| ATC_Code = L04AA10
| PubChem = 6436030
| Belstein Registry No. = 604010
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = C54H79NO13
| MolarMass = 914.172 g/mol
| Bioavailability = 20%, decreases after consumption of food rich in fat
| Protein_binding = 92%
| Metabolism = Hepatic
| Half_life = 57 - 63 hours
| Excretion = Mostly faecal
| Liscence data = EU / US
| Pregnancy_cat = C(AU) C(US)
| Legal_status = Rr only (US)
| Routes = Oral
}}

'''[[Other Properties: Optical Rotary Power]]'''

'''Type''': Alpha

'''Optical Rotary Power''': -58.2 degrees

'''Wavelength''': 589 nm

'''Temperature''': 298.15 K

'''[[Synthesis]]'''

Numerous total synthese of Rapamycin have been reported, on top of many part- and fragments- syntheses.

Rapamycin is a complex molecule, containing a 31-membered ring which includes a pipecolinyl group and pyranose ring, a conjugated triene system and a tri-carbonyl region. It also has 15 chiral centres, suggesting that the number of possible stereoisomers is enormous. The synthesis of Rapamycin hence poses a great challenge to synthetic chemists.

In the following synthesis, published in three separate papers, two fragments of C10-C21 and C22-C42 are formed separately, before being combined to give the total synthesis of rapamycin. Only the main outline of the synthesis will be illustrated on this page as it is too long and complex to show in great detail.

'''''Retro-synthesis'''''

In the retro-synthesis shown below, the molecule is disconnected at the ester group next to '''Carbon 1'''and the '''C21 - C22''' double bond of the triene, producing the synthetic precursors '''2''' and '''3'''. Further disconnections of '''3''' will be shown later. The '''C10-C21''' fragment is first synthesised.

[[Image: Rapamycin_retrosynthesis_eyk06.gif]]

'''''1. Synthesis of C10-C21 fragment'''''

The starting material of synthesis is (R)-methyl 3-hydroxy-2-methylpropionate '''''(8)'''''.

[[Image: Rapamycin_syn_1.gif]]

The starting material '''''(8)''''' is then converted to an alcohol in a '''four-step process'''.

1. Protection of the alcohol as aTHP ether, followed by

2. Reduction,

3. Ether formation and finally,

4. Deprotection steps.

Bromide '''''(9)''''' is formed with the substitution of the hydroxyl group in the product with a bromine. Subsequent reaction of '''''(9)''''' with methyl acetoacetate produced an ester, '''''(10) '''''.

[[Image: Rapamycin_syn_2.gif]]

Catalytic reduction of '''''(10)''''' under Noyori conditions yielded ester '''''(11)''''', which is later converted to its Weinreb amide '''''(12)'''''. Overall, percentage yield of compound '''''(12)''''' is 54%, from a relatively cheap starting material. Vinyl bromide, '''''(13)''''' was then metallated with t-BuLi and the resulting vinyllithium was then combined with '''''(12)''''' and the PMB-protecting group removed to produce '''''(14)'''''. The remaining carbonyl group in '''''(14) ''''' was selectively reduced to a hydroxyl group. In order to differentiate the 1,3-diol, a lactol was formed, where one hydroxyl group ended up in the ring. An oxidation was performed using RuCl2(PPh3)3 to form a lactol. The two remaining alcohol groups can then be methylated using MeI to give '''''(15)'''''.

[[Image: Rapamycin_syn_3.gif]]

The lactol ring opening was achieved using TiCl4 and thiol HS(CH2)2SH to form a dithiolane. The freed alcohol was then protected as its TBS ether and the same protecting group selectively removed from the primary alcohol to form '''''(16)'''''. To avoid removing the dithiolane group at a later stage in the synthesis, the thio-acetal was converted to the dimethyl acetal '''''(17)''''' using PhI(OCOCF3)2 and methanol.

[[Image: Rapamycin_syn_4.gif]]

The next stage in the synthesis was to extend '''''(17)''''' for the building of the triene region. The terminal alcohol was oxidised to its aldehyde using BaMnO4 , then a Wittig reaction was carried out using Ph3P=CHCO2Et and CH2Cl2 to form the second double bond. Reduction of the ester group to an alcohol was carried out using DIBAL-H, then treatment with PPh3. Susequent exposure to the air gave '''Rapamycin fragment 2'''.

'''''2. Synthesis of C22-C42 fragment'''''

Retrosynthesis of '''''(3)'''''gives the three synthetic '''''precursors 5, 6 and 7'''''.
It was thought '''''(4)''''' could be obtained by alkylative coupling of a vinyllithium species generated from '''''(7)''''' to the Weinreb amide '''''(6)'''''. The nucleophilic opening of epoxide '''''(5)''''' by the lithiated sulfone from phenyl sulfone ''(4)'' would then give the desired fragment.

[[Image: Rapamycin_syn_5.gif]]

The ester '''''(18)''''' was used as a starting material to make fragment '''''(6)'''''.

[[Image: Rapamycin_syn_6.gif]]

A Wittig reaction, followed by reduction and protection steps, give '''''(19)'''''. This was hydrogenated using a rhodium catalyst to give syn-dimethyl product '''''(20)'''''. The minor anti diastereomer was successfully separated off. '''''(20)''''' was oxidised, before undergoing an aldol condensation to give adduct '''''(21)'''''.

[[Image: Rapamycin_syn_7.gif]]

Transamination of '''''(21)'''''and protection of the alcohol with PMB produced amide '''''(6) text''''', corresponding to the C22-C28 segment of Rapamycin.

The vinyl bromide '''''(7)''''' was prepared using ester '''''(22)''''' as a starting material.

[[Image: Rapamycin_syn_8.gif]]

Reduction of '''''(22)''''', followed by dibromoolefination, led to product '''''(23)'''''. Acetylene '''''(24)''''' was prepared using n-BuLi, THF and MeI, then sulfenylation with Ph2S2 and bromination gave fragment '''''(7)'''''.

[[Image: Rapamycin_syn_9.gif]]

Iodination and alkylation of starting material '''''(25)''''' with the lithiated allylic sulfide shown followed by a number of further steps, resulted in its conversion to fragment '''''(5)'''''.

[[Image: Rapamycin_syn_10.gif]]

Fragments '''''(7)''''' was first converted to its vinyllithium using t-BuLi, then combined with '''''(6)''''' to form an enone of 78% yield. Stereoselective reduction of the carbonyl group using Zn(BH4)2 gave an alcohol which was protected with DEIPS giving '''''(28)'''''. The phenyl sulfide was oxidised to a sulfone using m-CPBA in excess pyridine.

[[Image: Rapamycin_syn_11.gif]]

Lithiation and addition of the epoxide '''''(50''''' resulted in the hydroxy sulfone in a 4:1 ratio of two diastereomers, which were separated by HPLC. Metalation using n-BuLi followed by oxidation formed the total C22-C42 fragment.

'''''3. Total Synthesis of Rapamycin using combination of C10-C21 and C22-C42 fragments '''''

Fragment '''''(3)''''' (C22-C42) was treated with (S)-Boc-pipecolinal, followed by a Swern oxidation, yielded the aldehyde '''''(29)'''''.

[[Image: Rapamycin_syn_12.gif]]

Condensation with the lithium salt of phosphine oxide 2 (C10-C21) produced the triene as shown below.

[[Image: Rapamycin_syn_13.gif]]

The triene was hydrolysed with pyridinium p-toluenesulfonic acid and an aldol reaction was performed. Treatment with triethylsilyl triflate produced an amino acid, which was subjected to Mukaiyama macrocyclization conditions to form the 31-membered ring.

Finally, deprotection steps were performed to give synthetic Rapamyin '''''(1)'''''. The identity of this Rapamycin sample is confirmed by comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.

'''[[Biological Mechanism]]'''

Rapamycin is believed to block the immune response by causing programmed cell death, otherwise known as apoptosis, in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle.

The diagram below illustrates the complex binding, where FKBP-12 is represented by the blue protein and FRAP the red protein, with Rapamycin between them.

[[Image: Rapamycin_biomech_eyk06.gif]]

This Rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1 of the cell cycle. Rapamycin hence stops the cell at the G1-S transition. As such, the proliferation of T-cells is stopped and apoptosis is induced instead.

Activation of T cells produce a small population of regulatory T cells, which possess the abilibty to control the other T cells that cause rejection. The apoptic death of the many rejection-causing T cells enables the regulatory T cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells though it does not block apoptosis.Therefore, by inducing apoptosis in rejection-causing T cells, Rapamycin can reduce the tendency to reject the transplant, yet allowing the body to develop a tolerance for it.

'''[[Cancer]]'''

Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. Usually, cancer is caused by a p53 mutation, where abnormal cells are prevented from dying by apoptosis. Instead they will continue to divide uncontrollably, reproducing and magnifying the error. Rapamycin could cease the division of cancer cells in a similar fashion in which it stops cell division in T-cells, and also cause apoptosis. It could hence be adminstered in the treatment of cancer.

Studies have revealed that Rapamycin is capable of inhibiting growth and induce cell death by apoptosis in B lymphoma cells.

'''[[References]]'''

http://www.ch.ic.ac.uk/local/projects/russell/index.html

http://en.wikipedia.org/wiki/Sirolimus

Rapamycin

2007-11-27T14:48:12Z

Eyk06: 3D structure of Rapamycin

'''[[Introduction]]'''

|<jmol>
<jmolApplet>
<title>Cyclopentasiloxane</title><color>black</color><size>400</size>
<script>zoom 90; cpk -25;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script>
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<uploadedFileContents>CIYSIM.cif</uploadedFileContents></jmolAppletButton>
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[[Image: Rapamycin_ball&stickstrt_eyk06.pnf]]

Rapamycin, also known as Sirolimus, is a peptide that was isolated in 1975 from the bacteria strain Streptomyces hygroscopicus found in a soil sample on Easter Island. It is a macrolide, hence accounting for the "-mycin" in its name.

Rapamycin has been discovered to behave interestingly, possessing a novel mechanism of immunosuppression. Its mode of action differs largely from the other immunosupressants available, bearing great promise for its potential uses and advantages over other treatments.It is currently used as a new immunosuppressant drug, adminstered to precent rejection during organ transplants, particularly kidney transplants. It received approval from the FDA in September 1999, and has since been marketed as an immunosuppresant under the tradename 'Rapamune' by Wyeth-Ayerest.

[[Image: Rapamycin_tradename_eyk06.gif]]

The general shortage of organs available for transplants spells greater need for adrug that boosts the chance of organ survival. Conventional treatments used, such as cyclosporin and FK506, are effective in ensuring the short-term survival of the transplant, but fail in ensuring the organ is accepted by the body in the long run. Rapamycin is hence very important in the treatment of organ transplant patients as it appears to have a different mechanism of action to cyclosporin and FK506, as discussed earlier. In addition,it results in fewer side effects than the standard anti-rejection treatments due to its novel mode of action. Finally, the cytotoxic properties of Rapamycin could also make it effective in the treatment of cancer as Rapamycin is antiproliferative in nature, and there is ongoing research in this field of medicine.

{{Drug-Box |
| Box_Name = Properties of Rapamycin
| ImageFile = [[Image: Rapamycin_chemstrt_eyk06_self.gif]]
| IUPACName = (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
| OtherName = Rapamune, Sirolimus
| CAS_No = 23123-88-9
| ATC_Code = L04AA10
| PubChem = 6436030
| Belstein Registry No. = 604010
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = C54H79NO13
| MolarMass = 914.172 g/mol
| Bioavailability = 20%, decreases after consumption of food rich in fat
| Protein_binding = 92%
| Metabolism = Hepatic
| Half_life = 57 - 63 hours
| Excretion = Mostly faecal
| Liscence data = EU / US
| Pregnancy_cat = C(AU) C(US)
| Legal_status = Rr only (US)
| Routes = Oral
}}

'''[[Other Properties: Optical Rotary Power]]'''

'''Type''': Alpha

'''Optical Rotary Power''': -58.2 degrees

'''Wavelength''': 589 nm

'''Temperature''': 298.15 K

'''[[Synthesis]]'''

Numerous total synthese of Rapamycin have been reported, on top of many part- and fragments- syntheses.

Rapamycin is a complex molecule, containing a 31-membered ring which includes a pipecolinyl group and pyranose ring, a conjugated triene system and a tri-carbonyl region. It also has 15 chiral centres, suggesting that the number of possible stereoisomers is enormous. The synthesis of Rapamycin hence poses a great challenge to synthetic chemists.

In the following synthesis, published in three separate papers, two fragments of C10-C21 and C22-C42 are formed separately, before being combined to give the total synthesis of rapamycin. Only the main outline of the synthesis will be illustrated on this page as it is too long and complex to show in great detail.

'''''Retro-synthesis'''''

In the retro-synthesis shown below, the molecule is disconnected at the ester group next to '''Carbon 1'''and the '''C21 - C22''' double bond of the triene, producing the synthetic precursors '''2''' and '''3'''. Further disconnections of '''3''' will be shown later. The '''C10-C21''' fragment is first synthesised.

[[Image: Rapamycin_retrosynthesis_eyk06.gif]]

'''''1. Synthesis of C10-C21 fragment'''''

The starting material of synthesis is (R)-methyl 3-hydroxy-2-methylpropionate '''''(8)'''''.

[[Image: Rapamycin_syn_1.gif]]

The starting material '''''(8)''''' is then converted to an alcohol in a '''four-step process'''.

1. Protection of the alcohol as aTHP ether, followed by

2. Reduction,

3. Ether formation and finally,

4. Deprotection steps.

Bromide '''''(9)''''' is formed with the substitution of the hydroxyl group in the product with a bromine. Subsequent reaction of '''''(9)''''' with methyl acetoacetate produced an ester, '''''(10) '''''.

[[Image: Rapamycin_syn_2.gif]]

Catalytic reduction of '''''(10)''''' under Noyori conditions yielded ester '''''(11)''''', which is later converted to its Weinreb amide '''''(12)'''''. Overall, percentage yield of compound '''''(12)''''' is 54%, from a relatively cheap starting material. Vinyl bromide, '''''(13)''''' was then metallated with t-BuLi and the resulting vinyllithium was then combined with '''''(12)''''' and the PMB-protecting group removed to produce '''''(14)'''''. The remaining carbonyl group in '''''(14) ''''' was selectively reduced to a hydroxyl group. In order to differentiate the 1,3-diol, a lactol was formed, where one hydroxyl group ended up in the ring. An oxidation was performed using RuCl2(PPh3)3 to form a lactol. The two remaining alcohol groups can then be methylated using MeI to give '''''(15)'''''.

[[Image: Rapamycin_syn_3.gif]]

The lactol ring opening was achieved using TiCl4 and thiol HS(CH2)2SH to form a dithiolane. The freed alcohol was then protected as its TBS ether and the same protecting group selectively removed from the primary alcohol to form '''''(16)'''''. To avoid removing the dithiolane group at a later stage in the synthesis, the thio-acetal was converted to the dimethyl acetal '''''(17)''''' using PhI(OCOCF3)2 and methanol.

[[Image: Rapamycin_syn_4.gif]]

The next stage in the synthesis was to extend '''''(17)''''' for the building of the triene region. The terminal alcohol was oxidised to its aldehyde using BaMnO4 , then a Wittig reaction was carried out using Ph3P=CHCO2Et and CH2Cl2 to form the second double bond. Reduction of the ester group to an alcohol was carried out using DIBAL-H, then treatment with PPh3. Susequent exposure to the air gave '''Rapamycin fragment 2'''.

'''''2. Synthesis of C22-C42 fragment'''''

Retrosynthesis of '''''(3)'''''gives the three synthetic '''''precursors 5, 6 and 7'''''.
It was thought '''''(4)''''' could be obtained by alkylative coupling of a vinyllithium species generated from '''''(7)''''' to the Weinreb amide '''''(6)'''''. The nucleophilic opening of epoxide '''''(5)''''' by the lithiated sulfone from phenyl sulfone ''(4)'' would then give the desired fragment.

[[Image: Rapamycin_syn_5.gif]]

The ester '''''(18)''''' was used as a starting material to make fragment '''''(6)'''''.

[[Image: Rapamycin_syn_6.gif]]

A Wittig reaction, followed by reduction and protection steps, give '''''(19)'''''. This was hydrogenated using a rhodium catalyst to give syn-dimethyl product '''''(20)'''''. The minor anti diastereomer was successfully separated off. '''''(20)''''' was oxidised, before undergoing an aldol condensation to give adduct '''''(21)'''''.

[[Image: Rapamycin_syn_7.gif]]

Transamination of '''''(21)'''''and protection of the alcohol with PMB produced amide '''''(6) text''''', corresponding to the C22-C28 segment of Rapamycin.

The vinyl bromide '''''(7)''''' was prepared using ester '''''(22)''''' as a starting material.

[[Image: Rapamycin_syn_8.gif]]

Reduction of '''''(22)''''', followed by dibromoolefination, led to product '''''(23)'''''. Acetylene '''''(24)''''' was prepared using n-BuLi, THF and MeI, then sulfenylation with Ph2S2 and bromination gave fragment '''''(7)'''''.

[[Image: Rapamycin_syn_9.gif]]

Iodination and alkylation of starting material '''''(25)''''' with the lithiated allylic sulfide shown followed by a number of further steps, resulted in its conversion to fragment '''''(5)'''''.

[[Image: Rapamycin_syn_10.gif]]

Fragments '''''(7)''''' was first converted to its vinyllithium using t-BuLi, then combined with '''''(6)''''' to form an enone of 78% yield. Stereoselective reduction of the carbonyl group using Zn(BH4)2 gave an alcohol which was protected with DEIPS giving '''''(28)'''''. The phenyl sulfide was oxidised to a sulfone using m-CPBA in excess pyridine.

[[Image: Rapamycin_syn_11.gif]]

Lithiation and addition of the epoxide '''''(50''''' resulted in the hydroxy sulfone in a 4:1 ratio of two diastereomers, which were separated by HPLC. Metalation using n-BuLi followed by oxidation formed the total C22-C42 fragment.

'''''3. Total Synthesis of Rapamycin using combination of C10-C21 and C22-C42 fragments '''''

Fragment '''''(3)''''' (C22-C42) was treated with (S)-Boc-pipecolinal, followed by a Swern oxidation, yielded the aldehyde '''''(29)'''''.

[[Image: Rapamycin_syn_12.gif]]

Condensation with the lithium salt of phosphine oxide 2 (C10-C21) produced the triene as shown below.

[[Image: Rapamycin_syn_13.gif]]

The triene was hydrolysed with pyridinium p-toluenesulfonic acid and an aldol reaction was performed. Treatment with triethylsilyl triflate produced an amino acid, which was subjected to Mukaiyama macrocyclization conditions to form the 31-membered ring.

Finally, deprotection steps were performed to give synthetic Rapamyin '''''(1)'''''. The identity of this Rapamycin sample is confirmed by comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.

'''[[Biological Mechanism]]'''

Rapamycin is believed to block the immune response by causing programmed cell death, otherwise known as apoptosis, in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle.

The diagram below illustrates the complex binding, where FKBP-12 is represented by the blue protein and FRAP the red protein, with Rapamycin between them.

[[Image: Rapamycin_biomech_eyk06.gif]]

This Rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1 of the cell cycle. Rapamycin hence stops the cell at the G1-S transition. As such, the proliferation of T-cells is stopped and apoptosis is induced instead.

Activation of T cells produce a small population of regulatory T cells, which possess the abilibty to control the other T cells that cause rejection. The apoptic death of the many rejection-causing T cells enables the regulatory T cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells though it does not block apoptosis.Therefore, by inducing apoptosis in rejection-causing T cells, Rapamycin can reduce the tendency to reject the transplant, yet allowing the body to develop a tolerance for it.

'''[[Cancer]]'''

Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. Usually, cancer is caused by a p53 mutation, where abnormal cells are prevented from dying by apoptosis. Instead they will continue to divide uncontrollably, reproducing and magnifying the error. Rapamycin could cease the division of cancer cells in a similar fashion in which it stops cell division in T-cells, and also cause apoptosis. It could hence be adminstered in the treatment of cancer.

Studies have revealed that Rapamycin is capable of inhibiting growth and induce cell death by apoptosis in B lymphoma cells.

File:32015.pdb

2007-11-27T14:46:34Z

Eyk06: structure of Rapamycin (3D structure)

structure of Rapamycin (3D structure)

Rapamycin

2007-11-27T14:45:04Z

Eyk06: chemdraw strt of Rapamycin

'''[[Introduction]]'''

|<jmol>
<jmolApplet>
<title>Cyclopentasiloxane</title><color>black</color><size>400</size>
<script>zoom 90; cpk -25;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script>
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</jmol>

[[Image: Rapamycin_ball&stickstrt_eyk06.pnf]]

Rapamycin, also known as Sirolimus, is a peptide that was isolated in 1975 from the bacteria strain Streptomyces hygroscopicus found in a soil sample on Easter Island. It is a macrolide, hence accounting for the "-mycin" in its name.

Rapamycin has been discovered to behave interestingly, possessing a novel mechanism of immunosuppression. Its mode of action differs largely from the other immunosupressants available, bearing great promise for its potential uses and advantages over other treatments.It is currently used as a new immunosuppressant drug, adminstered to precent rejection during organ transplants, particularly kidney transplants. It received approval from the FDA in September 1999, and has since been marketed as an immunosuppresant under the tradename 'Rapamune' by Wyeth-Ayerest.

[[Image: Rapamycin_tradename_eyk06.gif]]

The general shortage of organs available for transplants spells greater need for adrug that boosts the chance of organ survival. Conventional treatments used, such as cyclosporin and FK506, are effective in ensuring the short-term survival of the transplant, but fail in ensuring the organ is accepted by the body in the long run. Rapamycin is hence very important in the treatment of organ transplant patients as it appears to have a different mechanism of action to cyclosporin and FK506, as discussed earlier. In addition,it results in fewer side effects than the standard anti-rejection treatments due to its novel mode of action. Finally, the cytotoxic properties of Rapamycin could also make it effective in the treatment of cancer as Rapamycin is antiproliferative in nature, and there is ongoing research in this field of medicine.

{{Drug-Box |
| Box_Name = Properties of Rapamycin
| ImageFile = [[Image: Rapamycin_chemstrt_eyk06_self.gif]]
| IUPACName = (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
| OtherName = Rapamune, Sirolimus
| CAS_No = 23123-88-9
| ATC_Code = L04AA10
| PubChem = 6436030
| Belstein Registry No. = 604010
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = C54H79NO13
| MolarMass = 914.172 g/mol
| Bioavailability = 20%, decreases after consumption of food rich in fat
| Protein_binding = 92%
| Metabolism = Hepatic
| Half_life = 57 - 63 hours
| Excretion = Mostly faecal
| Liscence data = EU / US
| Pregnancy_cat = C(AU) C(US)
| Legal_status = Rr only (US)
| Routes = Oral
}}

'''[[Other Properties: Optical Rotary Power]]'''

'''Type''': Alpha

'''Optical Rotary Power''': -58.2 degrees

'''Wavelength''': 589 nm

'''Temperature''': 298.15 K

'''[[Synthesis]]'''

Numerous total synthese of Rapamycin have been reported, on top of many part- and fragments- syntheses.

Rapamycin is a complex molecule, containing a 31-membered ring which includes a pipecolinyl group and pyranose ring, a conjugated triene system and a tri-carbonyl region. It also has 15 chiral centres, suggesting that the number of possible stereoisomers is enormous. The synthesis of Rapamycin hence poses a great challenge to synthetic chemists.

In the following synthesis, published in three separate papers, two fragments of C10-C21 and C22-C42 are formed separately, before being combined to give the total synthesis of rapamycin. Only the main outline of the synthesis will be illustrated on this page as it is too long and complex to show in great detail.

'''''Retro-synthesis'''''

In the retro-synthesis shown below, the molecule is disconnected at the ester group next to '''Carbon 1'''and the '''C21 - C22''' double bond of the triene, producing the synthetic precursors '''2''' and '''3'''. Further disconnections of '''3''' will be shown later. The '''C10-C21''' fragment is first synthesised.

[[Image: Rapamycin_retrosynthesis_eyk06.gif]]

'''''1. Synthesis of C10-C21 fragment'''''

The starting material of synthesis is (R)-methyl 3-hydroxy-2-methylpropionate '''''(8)'''''.

[[Image: Rapamycin_syn_1.gif]]

The starting material '''''(8)''''' is then converted to an alcohol in a '''four-step process'''.

1. Protection of the alcohol as aTHP ether, followed by

2. Reduction,

3. Ether formation and finally,

4. Deprotection steps.

Bromide '''''(9)''''' is formed with the substitution of the hydroxyl group in the product with a bromine. Subsequent reaction of '''''(9)''''' with methyl acetoacetate produced an ester, '''''(10) '''''.

[[Image: Rapamycin_syn_2.gif]]

Catalytic reduction of '''''(10)''''' under Noyori conditions yielded ester '''''(11)''''', which is later converted to its Weinreb amide '''''(12)'''''. Overall, percentage yield of compound '''''(12)''''' is 54%, from a relatively cheap starting material. Vinyl bromide, '''''(13)''''' was then metallated with t-BuLi and the resulting vinyllithium was then combined with '''''(12)''''' and the PMB-protecting group removed to produce '''''(14)'''''. The remaining carbonyl group in '''''(14) ''''' was selectively reduced to a hydroxyl group. In order to differentiate the 1,3-diol, a lactol was formed, where one hydroxyl group ended up in the ring. An oxidation was performed using RuCl2(PPh3)3 to form a lactol. The two remaining alcohol groups can then be methylated using MeI to give '''''(15)'''''.

[[Image: Rapamycin_syn_3.gif]]

The lactol ring opening was achieved using TiCl4 and thiol HS(CH2)2SH to form a dithiolane. The freed alcohol was then protected as its TBS ether and the same protecting group selectively removed from the primary alcohol to form '''''(16)'''''. To avoid removing the dithiolane group at a later stage in the synthesis, the thio-acetal was converted to the dimethyl acetal '''''(17)''''' using PhI(OCOCF3)2 and methanol.

[[Image: Rapamycin_syn_4.gif]]

The next stage in the synthesis was to extend '''''(17)''''' for the building of the triene region. The terminal alcohol was oxidised to its aldehyde using BaMnO4 , then a Wittig reaction was carried out using Ph3P=CHCO2Et and CH2Cl2 to form the second double bond. Reduction of the ester group to an alcohol was carried out using DIBAL-H, then treatment with PPh3. Susequent exposure to the air gave '''Rapamycin fragment 2'''.

'''''2. Synthesis of C22-C42 fragment'''''

Retrosynthesis of '''''(3)'''''gives the three synthetic '''''precursors 5, 6 and 7'''''.
It was thought '''''(4)''''' could be obtained by alkylative coupling of a vinyllithium species generated from '''''(7)''''' to the Weinreb amide '''''(6)'''''. The nucleophilic opening of epoxide '''''(5)''''' by the lithiated sulfone from phenyl sulfone ''(4)'' would then give the desired fragment.

[[Image: Rapamycin_syn_5.gif]]

The ester '''''(18)''''' was used as a starting material to make fragment '''''(6)'''''.

[[Image: Rapamycin_syn_6.gif]]

A Wittig reaction, followed by reduction and protection steps, give '''''(19)'''''. This was hydrogenated using a rhodium catalyst to give syn-dimethyl product '''''(20)'''''. The minor anti diastereomer was successfully separated off. '''''(20)''''' was oxidised, before undergoing an aldol condensation to give adduct '''''(21)'''''.

[[Image: Rapamycin_syn_7.gif]]

Transamination of '''''(21)'''''and protection of the alcohol with PMB produced amide '''''(6) text''''', corresponding to the C22-C28 segment of Rapamycin.

The vinyl bromide '''''(7)''''' was prepared using ester '''''(22)''''' as a starting material.

[[Image: Rapamycin_syn_8.gif]]

Reduction of '''''(22)''''', followed by dibromoolefination, led to product '''''(23)'''''. Acetylene '''''(24)''''' was prepared using n-BuLi, THF and MeI, then sulfenylation with Ph2S2 and bromination gave fragment '''''(7)'''''.

[[Image: Rapamycin_syn_9.gif]]

Iodination and alkylation of starting material '''''(25)''''' with the lithiated allylic sulfide shown followed by a number of further steps, resulted in its conversion to fragment '''''(5)'''''.

[[Image: Rapamycin_syn_10.gif]]

Fragments '''''(7)''''' was first converted to its vinyllithium using t-BuLi, then combined with '''''(6)''''' to form an enone of 78% yield. Stereoselective reduction of the carbonyl group using Zn(BH4)2 gave an alcohol which was protected with DEIPS giving '''''(28)'''''. The phenyl sulfide was oxidised to a sulfone using m-CPBA in excess pyridine.

[[Image: Rapamycin_syn_11.gif]]

Lithiation and addition of the epoxide '''''(50''''' resulted in the hydroxy sulfone in a 4:1 ratio of two diastereomers, which were separated by HPLC. Metalation using n-BuLi followed by oxidation formed the total C22-C42 fragment.

'''''3. Total Synthesis of Rapamycin using combination of C10-C21 and C22-C42 fragments '''''

Fragment '''''(3)''''' (C22-C42) was treated with (S)-Boc-pipecolinal, followed by a Swern oxidation, yielded the aldehyde '''''(29)'''''.

[[Image: Rapamycin_syn_12.gif]]

Condensation with the lithium salt of phosphine oxide 2 (C10-C21) produced the triene as shown below.

[[Image: Rapamycin_syn_13.gif]]

The triene was hydrolysed with pyridinium p-toluenesulfonic acid and an aldol reaction was performed. Treatment with triethylsilyl triflate produced an amino acid, which was subjected to Mukaiyama macrocyclization conditions to form the 31-membered ring.

Finally, deprotection steps were performed to give synthetic Rapamyin '''''(1)'''''. The identity of this Rapamycin sample is confirmed by comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.

'''[[Biological Mechanism]]'''

Rapamycin is believed to block the immune response by causing programmed cell death, otherwise known as apoptosis, in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle.

The diagram below illustrates the complex binding, where FKBP-12 is represented by the blue protein and FRAP the red protein, with Rapamycin between them.

[[Image: Rapamycin_biomech_eyk06.gif]]

This Rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1 of the cell cycle. Rapamycin hence stops the cell at the G1-S transition. As such, the proliferation of T-cells is stopped and apoptosis is induced instead.

Activation of T cells produce a small population of regulatory T cells, which possess the abilibty to control the other T cells that cause rejection. The apoptic death of the many rejection-causing T cells enables the regulatory T cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells though it does not block apoptosis.Therefore, by inducing apoptosis in rejection-causing T cells, Rapamycin can reduce the tendency to reject the transplant, yet allowing the body to develop a tolerance for it.

'''[[Cancer]]'''

Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. Usually, cancer is caused by a p53 mutation, where abnormal cells are prevented from dying by apoptosis. Instead they will continue to divide uncontrollably, reproducing and magnifying the error. Rapamycin could cease the division of cancer cells in a similar fashion in which it stops cell division in T-cells, and also cause apoptosis. It could hence be adminstered in the treatment of cancer.

Studies have revealed that Rapamycin is capable of inhibiting growth and induce cell death by apoptosis in B lymphoma cells.

Rapamycin

2007-11-27T14:42:11Z

Eyk06: chemical structure of Rapamycin - chemdraw

'''[[Introduction]]'''

|<jmol>
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<uploadedFileContents>CIYSIM.cif</uploadedFileContents></jmolAppletButton>
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[[Image: Rapamycin_ball&stickstrt_eyk06.pnf]]

Rapamycin, also known as Sirolimus, is a peptide that was isolated in 1975 from the bacteria strain Streptomyces hygroscopicus found in a soil sample on Easter Island. It is a macrolide, hence accounting for the "-mycin" in its name.

Rapamycin has been discovered to behave interestingly, possessing a novel mechanism of immunosuppression. Its mode of action differs largely from the other immunosupressants available, bearing great promise for its potential uses and advantages over other treatments.It is currently used as a new immunosuppressant drug, adminstered to precent rejection during organ transplants, particularly kidney transplants. It received approval from the FDA in September 1999, and has since been marketed as an immunosuppresant under the tradename 'Rapamune' by Wyeth-Ayerest.

[[Image: Rapamycin_tradename_eyk06.gif]]

The general shortage of organs available for transplants spells greater need for adrug that boosts the chance of organ survival. Conventional treatments used, such as cyclosporin and FK506, are effective in ensuring the short-term survival of the transplant, but fail in ensuring the organ is accepted by the body in the long run. Rapamycin is hence very important in the treatment of organ transplant patients as it appears to have a different mechanism of action to cyclosporin and FK506, as discussed earlier. In addition,it results in fewer side effects than the standard anti-rejection treatments due to its novel mode of action. Finally, the cytotoxic properties of Rapamycin could also make it effective in the treatment of cancer as Rapamycin is antiproliferative in nature, and there is ongoing research in this field of medicine.

{{Drug-Box |
| Box_Name = Properties of Rapamycin
| ImageFile = Rapamycin_chemstrt_eyk06_self.gif
| IUPACName = (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
| OtherName = Rapamune, Sirolimus
| CAS_No = 23123-88-9
| ATC_Code = L04AA10
| PubChem = 6436030
| Belstein Registry No. = 604010
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = C54H79NO13
| MolarMass = 914.172 g/mol
| Bioavailability = 20%, decreases after consumption of food rich in fat
| Protein_binding = 92%
| Metabolism = Hepatic
| Half_life = 57 - 63 hours
| Excretion = Mostly faecal
| Liscence data = EU / US
| Pregnancy_cat = C(AU) C(US)
| Legal_status = Rr only (US)
| Routes = Oral
}}

'''[[Other Properties: Optical Rotary Power]]'''

'''Type''': Alpha

'''Optical Rotary Power''': -58.2 degrees

'''Wavelength''': 589 nm

'''Temperature''': 298.15 K

'''[[Synthesis]]'''

Numerous total synthese of Rapamycin have been reported, on top of many part- and fragments- syntheses.

Rapamycin is a complex molecule, containing a 31-membered ring which includes a pipecolinyl group and pyranose ring, a conjugated triene system and a tri-carbonyl region. It also has 15 chiral centres, suggesting that the number of possible stereoisomers is enormous. The synthesis of Rapamycin hence poses a great challenge to synthetic chemists.

In the following synthesis, published in three separate papers, two fragments of C10-C21 and C22-C42 are formed separately, before being combined to give the total synthesis of rapamycin. Only the main outline of the synthesis will be illustrated on this page as it is too long and complex to show in great detail.

'''''Retro-synthesis'''''

In the retro-synthesis shown below, the molecule is disconnected at the ester group next to '''Carbon 1'''and the '''C21 - C22''' double bond of the triene, producing the synthetic precursors '''2''' and '''3'''. Further disconnections of '''3''' will be shown later. The '''C10-C21''' fragment is first synthesised.

[[Image: Rapamycin_retrosynthesis_eyk06.gif]]

'''''1. Synthesis of C10-C21 fragment'''''

The starting material of synthesis is (R)-methyl 3-hydroxy-2-methylpropionate '''''(8)'''''.

[[Image: Rapamycin_syn_1.gif]]

The starting material '''''(8)''''' is then converted to an alcohol in a '''four-step process'''.

1. Protection of the alcohol as aTHP ether, followed by

2. Reduction,

3. Ether formation and finally,

4. Deprotection steps.

Bromide '''''(9)''''' is formed with the substitution of the hydroxyl group in the product with a bromine. Subsequent reaction of '''''(9)''''' with methyl acetoacetate produced an ester, '''''(10) '''''.

[[Image: Rapamycin_syn_2.gif]]

Catalytic reduction of '''''(10)''''' under Noyori conditions yielded ester '''''(11)''''', which is later converted to its Weinreb amide '''''(12)'''''. Overall, percentage yield of compound '''''(12)''''' is 54%, from a relatively cheap starting material. Vinyl bromide, '''''(13)''''' was then metallated with t-BuLi and the resulting vinyllithium was then combined with '''''(12)''''' and the PMB-protecting group removed to produce '''''(14)'''''. The remaining carbonyl group in '''''(14) ''''' was selectively reduced to a hydroxyl group. In order to differentiate the 1,3-diol, a lactol was formed, where one hydroxyl group ended up in the ring. An oxidation was performed using RuCl2(PPh3)3 to form a lactol. The two remaining alcohol groups can then be methylated using MeI to give '''''(15)'''''.

[[Image: Rapamycin_syn_3.gif]]

The lactol ring opening was achieved using TiCl4 and thiol HS(CH2)2SH to form a dithiolane. The freed alcohol was then protected as its TBS ether and the same protecting group selectively removed from the primary alcohol to form '''''(16)'''''. To avoid removing the dithiolane group at a later stage in the synthesis, the thio-acetal was converted to the dimethyl acetal '''''(17)''''' using PhI(OCOCF3)2 and methanol.

[[Image: Rapamycin_syn_4.gif]]

The next stage in the synthesis was to extend '''''(17)''''' for the building of the triene region. The terminal alcohol was oxidised to its aldehyde using BaMnO4 , then a Wittig reaction was carried out using Ph3P=CHCO2Et and CH2Cl2 to form the second double bond. Reduction of the ester group to an alcohol was carried out using DIBAL-H, then treatment with PPh3. Susequent exposure to the air gave '''Rapamycin fragment 2'''.

'''''2. Synthesis of C22-C42 fragment'''''

Retrosynthesis of '''''(3)'''''gives the three synthetic '''''precursors 5, 6 and 7'''''.
It was thought '''''(4)''''' could be obtained by alkylative coupling of a vinyllithium species generated from '''''(7)''''' to the Weinreb amide '''''(6)'''''. The nucleophilic opening of epoxide '''''(5)''''' by the lithiated sulfone from phenyl sulfone ''(4)'' would then give the desired fragment.

[[Image: Rapamycin_syn_5.gif]]

The ester '''''(18)''''' was used as a starting material to make fragment '''''(6)'''''.

[[Image: Rapamycin_syn_6.gif]]

A Wittig reaction, followed by reduction and protection steps, give '''''(19)'''''. This was hydrogenated using a rhodium catalyst to give syn-dimethyl product '''''(20)'''''. The minor anti diastereomer was successfully separated off. '''''(20)''''' was oxidised, before undergoing an aldol condensation to give adduct '''''(21)'''''.

[[Image: Rapamycin_syn_7.gif]]

Transamination of '''''(21)'''''and protection of the alcohol with PMB produced amide '''''(6) text''''', corresponding to the C22-C28 segment of Rapamycin.

The vinyl bromide '''''(7)''''' was prepared using ester '''''(22)''''' as a starting material.

[[Image: Rapamycin_syn_8.gif]]

Reduction of '''''(22)''''', followed by dibromoolefination, led to product '''''(23)'''''. Acetylene '''''(24)''''' was prepared using n-BuLi, THF and MeI, then sulfenylation with Ph2S2 and bromination gave fragment '''''(7)'''''.

[[Image: Rapamycin_syn_9.gif]]

Iodination and alkylation of starting material '''''(25)''''' with the lithiated allylic sulfide shown followed by a number of further steps, resulted in its conversion to fragment '''''(5)'''''.

[[Image: Rapamycin_syn_10.gif]]

Fragments '''''(7)''''' was first converted to its vinyllithium using t-BuLi, then combined with '''''(6)''''' to form an enone of 78% yield. Stereoselective reduction of the carbonyl group using Zn(BH4)2 gave an alcohol which was protected with DEIPS giving '''''(28)'''''. The phenyl sulfide was oxidised to a sulfone using m-CPBA in excess pyridine.

[[Image: Rapamycin_syn_11.gif]]

Lithiation and addition of the epoxide '''''(50''''' resulted in the hydroxy sulfone in a 4:1 ratio of two diastereomers, which were separated by HPLC. Metalation using n-BuLi followed by oxidation formed the total C22-C42 fragment.

'''''3. Total Synthesis of Rapamycin using combination of C10-C21 and C22-C42 fragments '''''

Fragment '''''(3)''''' (C22-C42) was treated with (S)-Boc-pipecolinal, followed by a Swern oxidation, yielded the aldehyde '''''(29)'''''.

[[Image: Rapamycin_syn_12.gif]]

Condensation with the lithium salt of phosphine oxide 2 (C10-C21) produced the triene as shown below.

[[Image: Rapamycin_syn_13.gif]]

The triene was hydrolysed with pyridinium p-toluenesulfonic acid and an aldol reaction was performed. Treatment with triethylsilyl triflate produced an amino acid, which was subjected to Mukaiyama macrocyclization conditions to form the 31-membered ring.

Finally, deprotection steps were performed to give synthetic Rapamyin '''''(1)'''''. The identity of this Rapamycin sample is confirmed by comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.

'''[[Biological Mechanism]]'''

Rapamycin is believed to block the immune response by causing programmed cell death, otherwise known as apoptosis, in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle.

The diagram below illustrates the complex binding, where FKBP-12 is represented by the blue protein and FRAP the red protein, with Rapamycin between them.

[[Image: Rapamycin_biomech_eyk06.gif]]

This Rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1 of the cell cycle. Rapamycin hence stops the cell at the G1-S transition. As such, the proliferation of T-cells is stopped and apoptosis is induced instead.

Activation of T cells produce a small population of regulatory T cells, which possess the abilibty to control the other T cells that cause rejection. The apoptic death of the many rejection-causing T cells enables the regulatory T cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells though it does not block apoptosis.Therefore, by inducing apoptosis in rejection-causing T cells, Rapamycin can reduce the tendency to reject the transplant, yet allowing the body to develop a tolerance for it.

'''[[Cancer]]'''

Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. Usually, cancer is caused by a p53 mutation, where abnormal cells are prevented from dying by apoptosis. Instead they will continue to divide uncontrollably, reproducing and magnifying the error. Rapamycin could cease the division of cancer cells in a similar fashion in which it stops cell division in T-cells, and also cause apoptosis. It could hence be adminstered in the treatment of cancer.

Studies have revealed that Rapamycin is capable of inhibiting growth and induce cell death by apoptosis in B lymphoma cells.

File:Rapamycin chemstrt eyk06 self.gif

2007-11-27T14:41:13Z

Eyk06: self drawn Chemical structure of Rapamycin

self drawn Chemical structure of Rapamycin

Rapamycin

2007-11-27T14:11:54Z

Eyk06:

'''[[Introduction]]'''

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<title>Cyclopentasiloxane</title><color>black</color><size>400</size>
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[[Image: Rapamycin_ball&stickstrt_eyk06.pnf]]

Rapamycin, also known as Sirolimus, is a peptide that was isolated in 1975 from the bacteria strain Streptomyces hygroscopicus found in a soil sample on Easter Island. It is a macrolide, hence accounting for the "-mycin" in its name.

Rapamycin has been discovered to behave interestingly, possessing a novel mechanism of immunosuppression. Its mode of action differs largely from the other immunosupressants available, bearing great promise for its potential uses and advantages over other treatments.It is currently used as a new immunosuppressant drug, adminstered to precent rejection during organ transplants, particularly kidney transplants. It received approval from the FDA in September 1999, and has since been marketed as an immunosuppresant under the tradename 'Rapamune' by Wyeth-Ayerest.

[[Image: Rapamycin_tradename_eyk06.gif]]

The general shortage of organs available for transplants spells greater need for adrug that boosts the chance of organ survival. Conventional treatments used, such as cyclosporin and FK506, are effective in ensuring the short-term survival of the transplant, but fail in ensuring the organ is accepted by the body in the long run. Rapamycin is hence very important in the treatment of organ transplant patients as it appears to have a different mechanism of action to cyclosporin and FK506, as discussed earlier. In addition,it results in fewer side effects than the standard anti-rejection treatments due to its novel mode of action. Finally, the cytotoxic properties of Rapamycin could also make it effective in the treatment of cancer as Rapamycin is antiproliferative in nature, and there is ongoing research in this field of medicine.

{{Drug-Box |
| Box_Name = Properties of Rapamycin
| ImageFile = Rapamycin_chemstrt_eyk06.pnf
| IUPACName = (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
| OtherName = Rapamune, Sirolimus
| CAS_No = 23123-88-9
| ATC_Code = L04AA10
| PubChem = 6436030
| Belstein Registry No. = 604010
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = C54H79NO13
| MolarMass = 914.172 g/mol
| Bioavailability = 20%, decreases after consumption of food rich in fat
| Protein_binding = 92%
| Metabolism = Hepatic
| Half_life = 57 - 63 hours
| Excretion = Mostly faecal
| Liscence data = EU / US
| Pregnancy_cat = C(AU) C(US)
| Legal_status = Rr only (US)
| Routes = Oral
}}

'''[[Other Properties: Optical Rotary Power]]'''

'''Type''': Alpha

'''Optical Rotary Power''': -58.2 degrees

'''Wavelength''': 589 nm

'''Temperature''': 298.15 K

'''[[Synthesis]]'''

Numerous total synthese of Rapamycin have been reported, on top of many part- and fragments- syntheses.

Rapamycin is a complex molecule, containing a 31-membered ring which includes a pipecolinyl group and pyranose ring, a conjugated triene system and a tri-carbonyl region. It also has 15 chiral centres, suggesting that the number of possible stereoisomers is enormous. The synthesis of Rapamycin hence poses a great challenge to synthetic chemists.

In the following synthesis, published in three separate papers, two fragments of C10-C21 and C22-C42 are formed separately, before being combined to give the total synthesis of rapamycin. Only the main outline of the synthesis will be illustrated on this page as it is too long and complex to show in great detail.

'''''Retro-synthesis'''''

In the retro-synthesis shown below, the molecule is disconnected at the ester group next to '''Carbon 1'''and the '''C21 - C22''' double bond of the triene, producing the synthetic precursors '''2''' and '''3'''. Further disconnections of '''3''' will be shown later. The '''C10-C21''' fragment is first synthesised.

[[Image: Rapamycin_retrosynthesis_eyk06.gif]]

'''''1. Synthesis of C10-C21 fragment'''''

The starting material of synthesis is (R)-methyl 3-hydroxy-2-methylpropionate '''''(8)'''''.

[[Image: Rapamycin_syn_1.gif]]

The starting material '''''(8)''''' is then converted to an alcohol in a '''four-step process'''.

1. Protection of the alcohol as aTHP ether, followed by

2. Reduction,

3. Ether formation and finally,

4. Deprotection steps.

Bromide '''''(9)''''' is formed with the substitution of the hydroxyl group in the product with a bromine. Subsequent reaction of '''''(9)''''' with methyl acetoacetate produced an ester, '''''(10) '''''.

[[Image: Rapamycin_syn_2.gif]]

Catalytic reduction of '''''(10)''''' under Noyori conditions yielded ester '''''(11)''''', which is later converted to its Weinreb amide '''''(12)'''''. Overall, percentage yield of compound '''''(12)''''' is 54%, from a relatively cheap starting material. Vinyl bromide, '''''(13)''''' was then metallated with t-BuLi and the resulting vinyllithium was then combined with '''''(12)''''' and the PMB-protecting group removed to produce '''''(14)'''''. The remaining carbonyl group in '''''(14) ''''' was selectively reduced to a hydroxyl group. In order to differentiate the 1,3-diol, a lactol was formed, where one hydroxyl group ended up in the ring. An oxidation was performed using RuCl2(PPh3)3 to form a lactol. The two remaining alcohol groups can then be methylated using MeI to give '''''(15)'''''.

[[Image: Rapamycin_syn_3.gif]]

The lactol ring opening was achieved using TiCl4 and thiol HS(CH2)2SH to form a dithiolane. The freed alcohol was then protected as its TBS ether and the same protecting group selectively removed from the primary alcohol to form '''''(16)'''''. To avoid removing the dithiolane group at a later stage in the synthesis, the thio-acetal was converted to the dimethyl acetal '''''(17)''''' using PhI(OCOCF3)2 and methanol.

[[Image: Rapamycin_syn_4.gif]]

The next stage in the synthesis was to extend '''''(17)''''' for the building of the triene region. The terminal alcohol was oxidised to its aldehyde using BaMnO4 , then a Wittig reaction was carried out using Ph3P=CHCO2Et and CH2Cl2 to form the second double bond. Reduction of the ester group to an alcohol was carried out using DIBAL-H, then treatment with PPh3. Susequent exposure to the air gave '''Rapamycin fragment 2'''.

'''''2. Synthesis of C22-C42 fragment'''''

Retrosynthesis of '''''(3)'''''gives the three synthetic '''''precursors 5, 6 and 7'''''.
It was thought '''''(4)''''' could be obtained by alkylative coupling of a vinyllithium species generated from '''''(7)''''' to the Weinreb amide '''''(6)'''''. The nucleophilic opening of epoxide '''''(5)''''' by the lithiated sulfone from phenyl sulfone ''(4)'' would then give the desired fragment.

[[Image: Rapamycin_syn_5.gif]]

The ester '''''(18)''''' was used as a starting material to make fragment '''''(6)'''''.

[[Image: Rapamycin_syn_6.gif]]

A Wittig reaction, followed by reduction and protection steps, give '''''(19)'''''. This was hydrogenated using a rhodium catalyst to give syn-dimethyl product '''''(20)'''''. The minor anti diastereomer was successfully separated off. '''''(20)''''' was oxidised, before undergoing an aldol condensation to give adduct '''''(21)'''''.

[[Image: Rapamycin_syn_7.gif]]

Transamination of '''''(21)'''''and protection of the alcohol with PMB produced amide '''''(6) text''''', corresponding to the C22-C28 segment of Rapamycin.

The vinyl bromide '''''(7)''''' was prepared using ester '''''(22)''''' as a starting material.

[[Image: Rapamycin_syn_8.gif]]

Reduction of '''''(22)''''', followed by dibromoolefination, led to product '''''(23)'''''. Acetylene '''''(24)''''' was prepared using n-BuLi, THF and MeI, then sulfenylation with Ph2S2 and bromination gave fragment '''''(7)'''''.

[[Image: Rapamycin_syn_9.gif]]

Iodination and alkylation of starting material '''''(25)''''' with the lithiated allylic sulfide shown followed by a number of further steps, resulted in its conversion to fragment '''''(5)'''''.

[[Image: Rapamycin_syn_10.gif]]

Fragments '''''(7)''''' was first converted to its vinyllithium using t-BuLi, then combined with '''''(6)''''' to form an enone of 78% yield. Stereoselective reduction of the carbonyl group using Zn(BH4)2 gave an alcohol which was protected with DEIPS giving '''''(28)'''''. The phenyl sulfide was oxidised to a sulfone using m-CPBA in excess pyridine.

[[Image: Rapamycin_syn_11.gif]]

Lithiation and addition of the epoxide '''''(50''''' resulted in the hydroxy sulfone in a 4:1 ratio of two diastereomers, which were separated by HPLC. Metalation using n-BuLi followed by oxidation formed the total C22-C42 fragment.

'''''3. Total Synthesis of Rapamycin using combination of C10-C21 and C22-C42 fragments '''''

Fragment '''''(3)''''' (C22-C42) was treated with (S)-Boc-pipecolinal, followed by a Swern oxidation, yielded the aldehyde '''''(29)'''''.

[[Image: Rapamycin_syn_12.gif]]

Condensation with the lithium salt of phosphine oxide 2 (C10-C21) produced the triene as shown below.

[[Image: Rapamycin_syn_13.gif]]

The triene was hydrolysed with pyridinium p-toluenesulfonic acid and an aldol reaction was performed. Treatment with triethylsilyl triflate produced an amino acid, which was subjected to Mukaiyama macrocyclization conditions to form the 31-membered ring.

Finally, deprotection steps were performed to give synthetic Rapamyin '''''(1)'''''. The identity of this Rapamycin sample is confirmed by comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.

'''[[Biological Mechanism]]'''

Rapamycin is believed to block the immune response by causing programmed cell death, otherwise known as apoptosis, in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle.

The diagram below illustrates the complex binding, where FKBP-12 is represented by the blue protein and FRAP the red protein, with Rapamycin between them.

[[Image: Rapamycin_biomech_eyk06.gif]]

This Rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1 of the cell cycle. Rapamycin hence stops the cell at the G1-S transition. As such, the proliferation of T-cells is stopped and apoptosis is induced instead.

Activation of T cells produce a small population of regulatory T cells, which possess the abilibty to control the other T cells that cause rejection. The apoptic death of the many rejection-causing T cells enables the regulatory T cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells though it does not block apoptosis.Therefore, by inducing apoptosis in rejection-causing T cells, Rapamycin can reduce the tendency to reject the transplant, yet allowing the body to develop a tolerance for it.

'''[[Cancer]]'''

Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. Usually, cancer is caused by a p53 mutation, where abnormal cells are prevented from dying by apoptosis. Instead they will continue to divide uncontrollably, reproducing and magnifying the error. Rapamycin could cease the division of cancer cells in a similar fashion in which it stops cell division in T-cells, and also cause apoptosis. It could hence be adminstered in the treatment of cancer.

Studies have revealed that Rapamycin is capable of inhibiting growth and induce cell death by apoptosis in B lymphoma cells.

File:Rapamycin eyk06.MOL

2007-11-27T14:07:44Z

Eyk06: strt of Rapamycin

strt of Rapamycin

Rapamycin

2007-11-27T14:04:42Z

Eyk06: tradename and ball&stick diagram

'''[[Introduction]]'''

[[Image: Rapamycin_ball&stickstrt_eyk06.pnf]]

Rapamycin, also known as Sirolimus, is a peptide that was isolated in 1975 from the bacteria strain Streptomyces hygroscopicus found in a soil sample on Easter Island. It is a macrolide, hence accounting for the "-mycin" in its name.

Rapamycin has been discovered to behave interestingly, possessing a novel mechanism of immunosuppression. Its mode of action differs largely from the other immunosupressants available, bearing great promise for its potential uses and advantages over other treatments.It is currently used as a new immunosuppressant drug, adminstered to precent rejection during organ transplants, particularly kidney transplants. It received approval from the FDA in September 1999, and has since been marketed as an immunosuppresant under the tradename 'Rapamune' by Wyeth-Ayerest.

[[Image: Rapamycin_tradename_eyk06.gif]]

The general shortage of organs available for transplants spells greater need for adrug that boosts the chance of organ survival. Conventional treatments used, such as cyclosporin and FK506, are effective in ensuring the short-term survival of the transplant, but fail in ensuring the organ is accepted by the body in the long run. Rapamycin is hence very important in the treatment of organ transplant patients as it appears to have a different mechanism of action to cyclosporin and FK506, as discussed earlier. In addition,it results in fewer side effects than the standard anti-rejection treatments due to its novel mode of action. Finally, the cytotoxic properties of Rapamycin could also make it effective in the treatment of cancer as Rapamycin is antiproliferative in nature, and there is ongoing research in this field of medicine.

{{Drug-Box |
| Box_Name = Properties of Rapamycin
| ImageFile = Rapamycin_chemstrt_eyk06.pnf
| IUPACName = (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
| OtherName = Rapamune, Sirolimus
| CAS_No = 23123-88-9
| ATC_Code = L04AA10
| PubChem = 6436030
| Belstein Registry No. = 604010
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = C54H79NO13
| MolarMass = 914.172 g/mol
| Bioavailability = 20%, decreases after consumption of food rich in fat
| Protein_binding = 92%
| Metabolism = Hepatic
| Half_life = 57 - 63 hours
| Excretion = Mostly faecal
| Liscence data = EU / US
| Pregnancy_cat = C(AU) C(US)
| Legal_status = Rr only (US)
| Routes = Oral
}}

'''[[Other Properties: Optical Rotary Power]]'''

'''Type''': Alpha

'''Optical Rotary Power''': -58.2 degrees

'''Wavelength''': 589 nm

'''Temperature''': 298.15 K

'''[[Synthesis]]'''

Numerous total synthese of Rapamycin have been reported, on top of many part- and fragments- syntheses.

Rapamycin is a complex molecule, containing a 31-membered ring which includes a pipecolinyl group and pyranose ring, a conjugated triene system and a tri-carbonyl region. It also has 15 chiral centres, suggesting that the number of possible stereoisomers is enormous. The synthesis of Rapamycin hence poses a great challenge to synthetic chemists.

In the following synthesis, published in three separate papers, two fragments of C10-C21 and C22-C42 are formed separately, before being combined to give the total synthesis of rapamycin. Only the main outline of the synthesis will be illustrated on this page as it is too long and complex to show in great detail.

'''''Retro-synthesis'''''

In the retro-synthesis shown below, the molecule is disconnected at the ester group next to '''Carbon 1'''and the '''C21 - C22''' double bond of the triene, producing the synthetic precursors '''2''' and '''3'''. Further disconnections of '''3''' will be shown later. The '''C10-C21''' fragment is first synthesised.

[[Image: Rapamycin_retrosynthesis_eyk06.gif]]

'''''1. Synthesis of C10-C21 fragment'''''

The starting material of synthesis is (R)-methyl 3-hydroxy-2-methylpropionate '''''(8)'''''.

[[Image: Rapamycin_syn_1.gif]]

The starting material '''''(8)''''' is then converted to an alcohol in a '''four-step process'''.

1. Protection of the alcohol as aTHP ether, followed by

2. Reduction,

3. Ether formation and finally,

4. Deprotection steps.

Bromide '''''(9)''''' is formed with the substitution of the hydroxyl group in the product with a bromine. Subsequent reaction of '''''(9)''''' with methyl acetoacetate produced an ester, '''''(10) '''''.

[[Image: Rapamycin_syn_2.gif]]

Catalytic reduction of '''''(10)''''' under Noyori conditions yielded ester '''''(11)''''', which is later converted to its Weinreb amide '''''(12)'''''. Overall, percentage yield of compound '''''(12)''''' is 54%, from a relatively cheap starting material. Vinyl bromide, '''''(13)''''' was then metallated with t-BuLi and the resulting vinyllithium was then combined with '''''(12)''''' and the PMB-protecting group removed to produce '''''(14)'''''. The remaining carbonyl group in '''''(14) ''''' was selectively reduced to a hydroxyl group. In order to differentiate the 1,3-diol, a lactol was formed, where one hydroxyl group ended up in the ring. An oxidation was performed using RuCl2(PPh3)3 to form a lactol. The two remaining alcohol groups can then be methylated using MeI to give '''''(15)'''''.

[[Image: Rapamycin_syn_3.gif]]

The lactol ring opening was achieved using TiCl4 and thiol HS(CH2)2SH to form a dithiolane. The freed alcohol was then protected as its TBS ether and the same protecting group selectively removed from the primary alcohol to form '''''(16)'''''. To avoid removing the dithiolane group at a later stage in the synthesis, the thio-acetal was converted to the dimethyl acetal '''''(17)''''' using PhI(OCOCF3)2 and methanol.

[[Image: Rapamycin_syn_4.gif]]

The next stage in the synthesis was to extend '''''(17)''''' for the building of the triene region. The terminal alcohol was oxidised to its aldehyde using BaMnO4 , then a Wittig reaction was carried out using Ph3P=CHCO2Et and CH2Cl2 to form the second double bond. Reduction of the ester group to an alcohol was carried out using DIBAL-H, then treatment with PPh3. Susequent exposure to the air gave '''Rapamycin fragment 2'''.

'''''2. Synthesis of C22-C42 fragment'''''

Retrosynthesis of '''''(3)'''''gives the three synthetic '''''precursors 5, 6 and 7'''''.
It was thought '''''(4)''''' could be obtained by alkylative coupling of a vinyllithium species generated from '''''(7)''''' to the Weinreb amide '''''(6)'''''. The nucleophilic opening of epoxide '''''(5)''''' by the lithiated sulfone from phenyl sulfone ''(4)'' would then give the desired fragment.

[[Image: Rapamycin_syn_5.gif]]

The ester '''''(18)''''' was used as a starting material to make fragment '''''(6)'''''.

[[Image: Rapamycin_syn_6.gif]]

A Wittig reaction, followed by reduction and protection steps, give '''''(19)'''''. This was hydrogenated using a rhodium catalyst to give syn-dimethyl product '''''(20)'''''. The minor anti diastereomer was successfully separated off. '''''(20)''''' was oxidised, before undergoing an aldol condensation to give adduct '''''(21)'''''.

[[Image: Rapamycin_syn_7.gif]]

Transamination of '''''(21)'''''and protection of the alcohol with PMB produced amide '''''(6) text''''', corresponding to the C22-C28 segment of Rapamycin.

The vinyl bromide '''''(7)''''' was prepared using ester '''''(22)''''' as a starting material.

[[Image: Rapamycin_syn_8.gif]]

Reduction of '''''(22)''''', followed by dibromoolefination, led to product '''''(23)'''''. Acetylene '''''(24)''''' was prepared using n-BuLi, THF and MeI, then sulfenylation with Ph2S2 and bromination gave fragment '''''(7)'''''.

[[Image: Rapamycin_syn_9.gif]]

Iodination and alkylation of starting material '''''(25)''''' with the lithiated allylic sulfide shown followed by a number of further steps, resulted in its conversion to fragment '''''(5)'''''.

[[Image: Rapamycin_syn_10.gif]]

Fragments '''''(7)''''' was first converted to its vinyllithium using t-BuLi, then combined with '''''(6)''''' to form an enone of 78% yield. Stereoselective reduction of the carbonyl group using Zn(BH4)2 gave an alcohol which was protected with DEIPS giving '''''(28)'''''. The phenyl sulfide was oxidised to a sulfone using m-CPBA in excess pyridine.

[[Image: Rapamycin_syn_11.gif]]

Lithiation and addition of the epoxide '''''(50''''' resulted in the hydroxy sulfone in a 4:1 ratio of two diastereomers, which were separated by HPLC. Metalation using n-BuLi followed by oxidation formed the total C22-C42 fragment.

'''''3. Total Synthesis of Rapamycin using combination of C10-C21 and C22-C42 fragments '''''

Fragment '''''(3)''''' (C22-C42) was treated with (S)-Boc-pipecolinal, followed by a Swern oxidation, yielded the aldehyde '''''(29)'''''.

[[Image: Rapamycin_syn_12.gif]]

Condensation with the lithium salt of phosphine oxide 2 (C10-C21) produced the triene as shown below.

[[Image: Rapamycin_syn_13.gif]]

The triene was hydrolysed with pyridinium p-toluenesulfonic acid and an aldol reaction was performed. Treatment with triethylsilyl triflate produced an amino acid, which was subjected to Mukaiyama macrocyclization conditions to form the 31-membered ring.

Finally, deprotection steps were performed to give synthetic Rapamyin '''''(1)'''''. The identity of this Rapamycin sample is confirmed by comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.

'''[[Biological Mechanism]]'''

Rapamycin is believed to block the immune response by causing programmed cell death, otherwise known as apoptosis, in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle.

The diagram below illustrates the complex binding, where FKBP-12 is represented by the blue protein and FRAP the red protein, with Rapamycin between them.

[[Image: Rapamycin_biomech_eyk06.gif]]

This Rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1 of the cell cycle. Rapamycin hence stops the cell at the G1-S transition. As such, the proliferation of T-cells is stopped and apoptosis is induced instead.

Activation of T cells produce a small population of regulatory T cells, which possess the abilibty to control the other T cells that cause rejection. The apoptic death of the many rejection-causing T cells enables the regulatory T cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells though it does not block apoptosis.Therefore, by inducing apoptosis in rejection-causing T cells, Rapamycin can reduce the tendency to reject the transplant, yet allowing the body to develop a tolerance for it.

'''[[Cancer]]'''

Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. Usually, cancer is caused by a p53 mutation, where abnormal cells are prevented from dying by apoptosis. Instead they will continue to divide uncontrollably, reproducing and magnifying the error. Rapamycin could cease the division of cancer cells in a similar fashion in which it stops cell division in T-cells, and also cause apoptosis. It could hence be adminstered in the treatment of cancer.

Studies have revealed that Rapamycin is capable of inhibiting growth and induce cell death by apoptosis in B lymphoma cells.

File:Rapamycin tradename eyk06.gif

2007-11-27T14:03:06Z

Eyk06: Tradename of Rapamycin - Rapamune

Tradename of Rapamycin - Rapamune

File:Rapamycin ball&stickstrt eyk06.pnf

2007-11-27T14:00:41Z

Eyk06: Ball and stick structure of Rapamycin

Ball and stick structure of Rapamycin

Rapamycin

2007-11-27T13:57:22Z

Eyk06: Cancer

'''[[Introduction]]'''

Rapamycin, also known as Sirolimus, is a peptide that was isolated in 1975 from the bacteria strain Streptomyces hygroscopicus found in a soil sample on Easter Island. It is a macrolide, hence accounting for the "-mycin" in its name.

Rapamycin has been discovered to behave interestingly, possessing a novel mechanism of immunosuppression. Its mode of action differs largely from the other immunosupressants available, bearing great promise for its potential uses and advantages over other treatments.It is currently used as a new immunosuppressant drug, adminstered to precent rejection during organ transplants, particularly kidney transplants. It received approval from the FDA in September 1999, and has since been marketed as an immunosuppresant under the tradename 'Rapamune' by Wyeth-Ayerest.

The general shortage of organs available for transplants spells greater need for adrug that boosts the chance of organ survival. Conventional treatments used, such as cyclosporin and FK506, are effective in ensuring the short-term survival of the transplant, but fail in ensuring the organ is accepted by the body in the long run. Rapamycin is hence very important in the treatment of organ transplant patients as it appears to have a different mechanism of action to cyclosporin and FK506, as discussed earlier. In addition,it results in fewer side effects than the standard anti-rejection treatments due to its novel mode of action. Finally, the cytotoxic properties of Rapamycin could also make it effective in the treatment of cancer as Rapamycin is antiproliferative in nature, and there is ongoing research in this field of medicine.

{{Drug-Box |
| Box_Name = Properties of Rapamycin
| ImageFile = Rapamycin_chemstrt_eyk06.pnf
| IUPACName = (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
oxaazacyclohentriacontine-1,5,11,28,29
(4H,6H,31H)-pentone
| OtherName = Rapamune, Sirolimus
| CAS_No = 23123-88-9
| ATC_Code = L04AA10
| PubChem = 6436030
| Belstein Registry No. = 604010
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = C54H79NO13
| MolarMass = 914.172 g/mol
| Bioavailability = 20%, decreases after consumption of food rich in fat
| Protein_binding = 92%
| Metabolism = Hepatic
| Half_life = 57 - 63 hours
| Excretion = Mostly faecal
| Liscence data = EU / US
| Pregnancy_cat = C(AU) C(US)
| Legal_status = Rr only (US)
| Routes = Oral
}}

'''[[Other Properties: Optical Rotary Power]]'''

'''Type''': Alpha

'''Optical Rotary Power''': -58.2 degrees

'''Wavelength''': 589 nm

'''Temperature''': 298.15 K

'''[[Synthesis]]'''

Numerous total synthese of Rapamycin have been reported, on top of many part- and fragments- syntheses.

Rapamycin is a complex molecule, containing a 31-membered ring which includes a pipecolinyl group and pyranose ring, a conjugated triene system and a tri-carbonyl region. It also has 15 chiral centres, suggesting that the number of possible stereoisomers is enormous. The synthesis of Rapamycin hence poses a great challenge to synthetic chemists.

In the following synthesis, published in three separate papers, two fragments of C10-C21 and C22-C42 are formed separately, before being combined to give the total synthesis of rapamycin. Only the main outline of the synthesis will be illustrated on this page as it is too long and complex to show in great detail.

'''''Retro-synthesis'''''

In the retro-synthesis shown below, the molecule is disconnected at the ester group next to '''Carbon 1'''and the '''C21 - C22''' double bond of the triene, producing the synthetic precursors '''2''' and '''3'''. Further disconnections of '''3''' will be shown later. The '''C10-C21''' fragment is first synthesised.

[[Image: Rapamycin_retrosynthesis_eyk06.gif]]

'''''1. Synthesis of C10-C21 fragment'''''

The starting material of synthesis is (R)-methyl 3-hydroxy-2-methylpropionate '''''(8)'''''.

[[Image: Rapamycin_syn_1.gif]]

The starting material '''''(8)''''' is then converted to an alcohol in a '''four-step process'''.

1. Protection of the alcohol as aTHP ether, followed by

2. Reduction,

3. Ether formation and finally,

4. Deprotection steps.

Bromide '''''(9)''''' is formed with the substitution of the hydroxyl group in the product with a bromine. Subsequent reaction of '''''(9)''''' with methyl acetoacetate produced an ester, '''''(10) '''''.

[[Image: Rapamycin_syn_2.gif]]

Catalytic reduction of '''''(10)''''' under Noyori conditions yielded ester '''''(11)''''', which is later converted to its Weinreb amide '''''(12)'''''. Overall, percentage yield of compound '''''(12)''''' is 54%, from a relatively cheap starting material. Vinyl bromide, '''''(13)''''' was then metallated with t-BuLi and the resulting vinyllithium was then combined with '''''(12)''''' and the PMB-protecting group removed to produce '''''(14)'''''. The remaining carbonyl group in '''''(14) ''''' was selectively reduced to a hydroxyl group. In order to differentiate the 1,3-diol, a lactol was formed, where one hydroxyl group ended up in the ring. An oxidation was performed using RuCl2(PPh3)3 to form a lactol. The two remaining alcohol groups can then be methylated using MeI to give '''''(15)'''''.

[[Image: Rapamycin_syn_3.gif]]

The lactol ring opening was achieved using TiCl4 and thiol HS(CH2)2SH to form a dithiolane. The freed alcohol was then protected as its TBS ether and the same protecting group selectively removed from the primary alcohol to form '''''(16)'''''. To avoid removing the dithiolane group at a later stage in the synthesis, the thio-acetal was converted to the dimethyl acetal '''''(17)''''' using PhI(OCOCF3)2 and methanol.

[[Image: Rapamycin_syn_4.gif]]

The next stage in the synthesis was to extend '''''(17)''''' for the building of the triene region. The terminal alcohol was oxidised to its aldehyde using BaMnO4 , then a Wittig reaction was carried out using Ph3P=CHCO2Et and CH2Cl2 to form the second double bond. Reduction of the ester group to an alcohol was carried out using DIBAL-H, then treatment with PPh3. Susequent exposure to the air gave '''Rapamycin fragment 2'''.

'''''2. Synthesis of C22-C42 fragment'''''

Retrosynthesis of '''''(3)'''''gives the three synthetic '''''precursors 5, 6 and 7'''''.
It was thought '''''(4)''''' could be obtained by alkylative coupling of a vinyllithium species generated from '''''(7)''''' to the Weinreb amide '''''(6)'''''. The nucleophilic opening of epoxide '''''(5)''''' by the lithiated sulfone from phenyl sulfone ''(4)'' would then give the desired fragment.

[[Image: Rapamycin_syn_5.gif]]

The ester '''''(18)''''' was used as a starting material to make fragment '''''(6)'''''.

[[Image: Rapamycin_syn_6.gif]]

A Wittig reaction, followed by reduction and protection steps, give '''''(19)'''''. This was hydrogenated using a rhodium catalyst to give syn-dimethyl product '''''(20)'''''. The minor anti diastereomer was successfully separated off. '''''(20)''''' was oxidised, before undergoing an aldol condensation to give adduct '''''(21)'''''.

[[Image: Rapamycin_syn_7.gif]]

Transamination of '''''(21)'''''and protection of the alcohol with PMB produced amide '''''(6) text''''', corresponding to the C22-C28 segment of Rapamycin.

The vinyl bromide '''''(7)''''' was prepared using ester '''''(22)''''' as a starting material.

[[Image: Rapamycin_syn_8.gif]]

Reduction of '''''(22)''''', followed by dibromoolefination, led to product '''''(23)'''''. Acetylene '''''(24)''''' was prepared using n-BuLi, THF and MeI, then sulfenylation with Ph2S2 and bromination gave fragment '''''(7)'''''.

[[Image: Rapamycin_syn_9.gif]]

Iodination and alkylation of starting material '''''(25)''''' with the lithiated allylic sulfide shown followed by a number of further steps, resulted in its conversion to fragment '''''(5)'''''.

[[Image: Rapamycin_syn_10.gif]]

Fragments '''''(7)''''' was first converted to its vinyllithium using t-BuLi, then combined with '''''(6)''''' to form an enone of 78% yield. Stereoselective reduction of the carbonyl group using Zn(BH4)2 gave an alcohol which was protected with DEIPS giving '''''(28)'''''. The phenyl sulfide was oxidised to a sulfone using m-CPBA in excess pyridine.

[[Image: Rapamycin_syn_11.gif]]

Lithiation and addition of the epoxide '''''(50''''' resulted in the hydroxy sulfone in a 4:1 ratio of two diastereomers, which were separated by HPLC. Metalation using n-BuLi followed by oxidation formed the total C22-C42 fragment.

'''''3. Total Synthesis of Rapamycin using combination of C10-C21 and C22-C42 fragments '''''

Fragment '''''(3)''''' (C22-C42) was treated with (S)-Boc-pipecolinal, followed by a Swern oxidation, yielded the aldehyde '''''(29)'''''.

[[Image: Rapamycin_syn_12.gif]]

Condensation with the lithium salt of phosphine oxide 2 (C10-C21) produced the triene as shown below.

[[Image: Rapamycin_syn_13.gif]]

The triene was hydrolysed with pyridinium p-toluenesulfonic acid and an aldol reaction was performed. Treatment with triethylsilyl triflate produced an amino acid, which was subjected to Mukaiyama macrocyclization conditions to form the 31-membered ring.

Finally, deprotection steps were performed to give synthetic Rapamyin '''''(1)'''''. The identity of this Rapamycin sample is confirmed by comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.

'''[[Biological Mechanism]]'''

Rapamycin is believed to block the immune response by causing programmed cell death, otherwise known as apoptosis, in T cells. Rapamycin penetrates the cell membrane of T-cells and binds to an intracellular receptor called FKBP (FK506 Binding Protein). This complex then binds to FRAP (FKBP Rapamycin Associated Protein), a regulator of the G1 phase of the cell cycle.

The diagram below illustrates the complex binding, where FKBP-12 is represented by the blue protein and FRAP the red protein, with Rapamycin between them.

[[Image: Rapamycin_biomech_eyk06.gif]]

This Rapamycin complex inhibits the T cell response to IL-2, the substance which triggers T cells already activated by the TCR to progress through G1 of the cell cycle. Rapamycin hence stops the cell at the G1-S transition. As such, the proliferation of T-cells is stopped and apoptosis is induced instead.

Activation of T cells produce a small population of regulatory T cells, which possess the abilibty to control the other T cells that cause rejection. The apoptic death of the many rejection-causing T cells enables the regulatory T cells to override the rejection process. Rapamycin blocks the proliferation of activated T cells though it does not block apoptosis.Therefore, by inducing apoptosis in rejection-causing T cells, Rapamycin can reduce the tendency to reject the transplant, yet allowing the body to develop a tolerance for it.

'''[[Cancer]]'''

Cell division is controlled by cyclin dependent kinases, cyclins and p53, a protein which blocks the cell cycle if the DNA is damaged, leading to apoptosis. Usually, cancer is caused by a p53 mutation, where abnormal cells are prevented from dying by apoptosis. Instead they will continue to divide uncontrollably, reproducing and magnifying the error. Rapamycin could cease the division of cancer cells in a similar fashion in which it stops cell division in T-cells, and also cause apoptosis. It could hence be adminstered in the treatment of cancer.

Studies have revealed that Rapamycin is capable of inhibiting growth and induce cell death by apoptosis in B lymphoma cells.

Rapamycin

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Eyk06: Biological mechanism of Rapamycin

File:Rapamycin biomech eyk06.gif

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Eyk06: Biological mechanism

Biological mechanism

Rapamycin

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Eyk06: Synthesis of Rapamycin

File:Rapamycin syn 13.gif

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Eyk06: Step 13

Step 13

File:Rapamycin syn 12.gif

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Eyk06: Step 12

Step 12

File:Rapamycin syn 11.gif

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Eyk06: Step 11

Step 11

File:Rapamycin syn 10.gif

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Eyk06: Step 10

Step 10

File:Rapamycin syn 9.gif

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Eyk06: Step 9

Step 9

File:Rapamycin syn 8.gif

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Eyk06: Step 8

Step 8

File:Rapamycin syn 7.gif

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Eyk06: Step 7

Step 7

File:Rapamycin syn 6.gif

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Eyk06: Step 6

Step 6

File:Rapamycin syn 5.gif

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Eyk06: Step 5

Step 5