Drugs Tamoxifen

Entry 5 in Scheme 11.4 is a step in the synthesis of the anticancer drug tamoxifen. Explain why the 2-phenylbutanoyl group is introduced in preference to a trifluoroacetyl group. 

Custodio JB, Almeida LM, Madeira VM (1993) The active metabolite hydroxytamoxifen of the anticancer drug tamoxifen induces structural changes in membranes. Biochim Biophys Acta 1153(2) 308-314... 

De Medina P, Favre G, Poirot M (2004a) Multiple targeting by the antitumor drug tamoxifen a structure-activity study. Curr Med Chem Anti-Cancer Agents 4(6) 491-508... 

Table 7.2 The Carcinogenic Effects of the Drug Tamoxifen in Rats...

Bilensoy, E., Dogan, A. L., Sen, M., and Hincal, A. A. (2007), Complexation behaviour of antiestrogen drug tamoxifen citrate with natural and modified cyclodextrins, J. Indus. Phenom. Macroc. Chem., 57, 651-655. 

Other examples of arrays of biologically active compounds accessed through a multi-step RASP approach, include the synthesis of cysteine protease inhibitors by Ellman, and Armstrong s synthesis of a 25-membered array of analogues of the breast cancer drug Tamoxifen. " ... 

Treatment of ketone A with LDA followed by CH3CH2I did not form the desired alkylation product B. What product was formed instead Devise a muitistep method to convert A to B, a synthetic intermediate used to prepare the anticancer drug tamoxifen (Section 23.8C and the chapter-opening moiecule). 

Gao S, Singh J. In vitro percutaneous absorption enhancement of the lipophilic drug tamoxifen by terpenes. / Control Release 1998 51 193-199. 

It should be obvious that the cis isomer is usually also the (Z) isomer, while the trans isomer is usually also the (E) isomer. This useful arrangement is not foolproof, however, and the anticancer drug tamoxifen is a notable example of a drug that is trans with respect to the phenyl groups, but also (Z) when the Cahn-Ingold-Prelog priorities are used (Figure 4.17). 

The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis, 14, 315-317. 

Figure 7.11. 8-Methoxypsoralen (8-MOP) is oxidized to an epoxide, and either the epoxide or a ring-opened product derived from it is responsible for inactivation of P450. The structures of two drugs, tamoxifen and carbamazepine (CBZ), that inactivate P450 by unknown mechanisms are also shown.

Tamoxifen. The antiestrogenic drug, tamoxifen, is used in the treatment of advanced breast cancer, although it fi-equently causes steatosis in overweight women (Bruno et al. 2005). This cationic amphiphilic drug accumulates electro-phoretically in mitochondria, where it directly inhibits mitochondrial respiratiOTi and mitochondrial (3-oxidation, thus causing steatosis (Larosche et al. 2007). 

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