Anticancer 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... 

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). 

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). 

Hydroxyferrocifen related to the anticancer drug tamoxifen in which a ferrocenyl group has replaced a phenyl substituent with benefit on the cytotoxicity... 

Structurally related to the phytoalexins resveratrol and pterostilbene. Resveratrol is found in the skins of red grapes, other fruits and red wine, while pterostilbene is found in grapes and blueberries. Resveratrol possesses oestrogenic activity and has been investigated for anticancer activity. These compounds also have structural similarities with the anticancer drug tamoxifen (Figure 13.22). 

The application of organometallic complexes of the other group 8 elements, iron and osmium, in anticancer drug design has until recently been almost exclusively focused on iron, with the ferrocenyl derivative of tamoxifen (ferrocifen) being the most prominent example (104). Organometallic osmium compounds have been little explored in this respect. 

Morales L, Neven P, Timmerman D, Christiaens MR, Vergote I, Van Limbergen E, et al. (2004) Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients. Anticancer Drugs 15 753-760... 

Anticancer drugs Paclitaxel Docetaxel Vinblastine Vincristine Tipifarnib Diflomotecan Iiinotecan Doxorubicin Daunorubicin Etoposide Tenoposide Tamoxifen (i)... 

Vitamin E, in vitro, has been shown to enhance the cytotoxic effect of several anticancer drugs, including 5-fluorouracil (5-FU), doxorubicin, vincristine, dacarbazine, cisplatin, and tamoxifen. 

A similar difference has been observed for Kp M values of the anticancer drags tamoxifen and 4-hydroxytamoxifen determined in mitochondria, sarcoplasmic reticulum, and in liposomes made from lipids extracted from the corresponding native membranes [85]. The largest Kp M was observed in mitochondria, followed by sarcoplasmic reticulum and liposomes. The authors introduced for these experiments derivative spectroscopy, a reliable and rapid procedure to estimate drag partitioning into biomembranes. The method used the shift in the absorption spectra of the drug when removed from the aqueous phase to a hydrophobic environment (see Section 3.10). 

Foster AB, McCague R, Seago A, Leclercq G, Stoessel S, Roy F (1986) Modification of the basic side chain in tamoxifen effects on microsomal metabolism and in vitro biological activity. Anticancer Drug Des 1 245-257... 

The correct choice = E. Tamoxifen forms a complex with the estrogen receptor. Procarbazine inhibits monoamine oxidase, an enzyme required to metabolize tyramine found in fermentative sources, such as cheese and some wines. X-irradiation is effective in eradicating leukemic cells which have found sanctuary in the CNS. Many anticancer drugs are mutagenic and carcinogenic, particularly the alkylating agents. 

Tamoxifen is a potent anticancer drug used widely in the treatment of breast cancer. Tamoxifen binds to estrogen receptors, and in this way inhibits the growth of breast cancers that are estrogen dependent. One method to synthesize tamoxifen forms a new carbon-carbon bond on the a carbon to a carbonyl group using an intermediate enolate. In Chapter 23 we learn about these and other carbon-carbon bond-forming reactions that occur on the a carbon. 

Tamoxifen, the chapter-opening molecule, is a potent anticancer drug that has been used to treat certain forms of breast cancer for many years. One step in the synthesis of tamoxifen involves the treatment of ketone A with NaH as base to form an enolate. Alkylation of this enolate with CH3CH2I forms B in high yield. B is converted to tamoxifen in several steps, some of which are reactions you have already learned. 

The synthesis of tamoxifen, an anticancer drug used in the treatment of breast cancer (Opener, Section 23.8C)... 

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