Tamoxifen

Structures and 3D Image

Structure of Tamoxifen ^1,2

Chemical Information

IUPAC name	(Z) 2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethanamine.
Chemical Formula	C₂₆H₂₉NO
Molecular Weight	371.52 g mol^-1
Melting Point	96-98^oC
Type of Substance	White, Odourless Crystals

What is Tamoxifen Used For?

Tamoxifen is currently the most popular drug used for the treatment of breast cancer in women. Tamoxifen was discovered by AstraZeneca (formally known as ICI Pharmaceuticals) and is commercially known as Nolvadex, Istubal and Valodex. It is taken as a tablet

It has also been found that Tamoxifen can be used to treat other ailments, such as osteoporosis and gynecomastia in men.

Tamoxifen is occasionally used to improve the rare condition known as retroperitoneal fibrosis (or Ormond's disease), although the exact mechanism of this reaction is still unknown. This condition involves an excess of fibrous tissue and scar tissue in the part of the body which contains the kidneys, aorta, renal tract and various other structures. Symptoms of the condition improved within weeks, and within months signs of inflammation decreased and the scar tissue shrunk.

How Does Tamoxifen Work?

The primary function of Tamoxifen is as an anti-oestrogen drug, which means it reduces or stops the action of oestrogen.3

Breast cancer is hormone-related and relies on the supply of sex hormones, particularly oestrogen, to grow. Cancers with oestrogen receptors on the surface of their cells are called `oestrogen receptor positive' (ER positive). Oestrogen can fit directly into the active site on these receptors and causes the cells to divide and the tumour to grow (see Figure 1).4

Tamoxifen has a similar structure to oestrogen and works by imitating the action of oestrogen and fits into the active sites of the receptors. However, tamoxifen does not cause the cells to divide, but remains in place and prevents the oestrogen from getting to the cancer cells, therefore they either grow more slowly or stop growing altogether (see Figure 2).

How is Tamoxifen made?

Synthesis of Tamoxifen via a carbometalation of alkynylsilanes

Step 1

This is the 1st step in this synthesis. The reagents are Et₂AlCl, Cp₂TiCl₂, CH₂Cl₂. The product of this step in the reaction is then cleaved with NBS (N-bromosuccinimide)at -78^oC or 195.15K. The yield for this step is shown below the arrow.

Step 2

This is the next step in the synthesis of tamoxifen. The reagents are PhZnCl, Pd(PPh₃)₄ (this is the catalyst), THF, and this is under reflux.

Step 3

The reagents for the step are Br₂, CH₂Cl, NaOMe/MeOH, Temperature is -78^oC to Room Temperature

Step 4

The reagents are p-MeOC , H₄ZnCl, Pd(PPh₃)₄ (this is the catalyst), THF. The reaction happens under reflux.

Step 5

This last step takes place in 4 smaller steps. The 1 of these steps has the reagents NaSEt, DMF, and takes place under reflux. 2nd has reagents ClCH₃, CH₂NMe₂, HCl, NaOEt, EtOH and also takes place under reflux conditions. 3rd: HCl_(g) Et₂O. The last step has reagent 0.5M NaOH ⁶

Side Effects of using Tamoxifen

The most common side-effects of taking Tamoxifen in pre-menopausal women are:

nausea
hot flushes and sweats

some less common side-effects include

headaches
tiredness
dizziness.

For post-menopausal women who take Tamoxifen over a long period of time, there is a slightly increased risk of developing endometrial cancer, however, if detected early, treatment for this is usually successful and the benefits of taking Tamoxifen in treating breast-cancer far outweigh this small risk.5

References

1 - MDS Crossfire Commander Beilstein: Structure
2 - Conquest (Cambridge Crystal Structure Database): 3D image
3 - www.cancer-info.com/tamoxifen.htm
4 - www.fareston.com/d_living/d3.html
5 - www.cancerbackup.org.uk/Treatments/Hormonaltherapies/Individualhormonaltherapies/Tamoxifen
6 - R. Bryan Miller, Mohammed I. Al-Hassan Stereospecific Synthesis of (Z) - Tamoxifen via Carbometalation of Alkynylsilanes J. Org. Chem. 1985 50, 2121-2123
7 - http://www.annals.org/cgi/content/full/144/2/I-51
8 - http://en.wikipedia.org/wiki/Retroperitoneal_fibrosis