Tamoxifen conversion

It has been suggested that tamoxifen, one of the most effective therapeutic and chemopreventive agent for breast cancer, modulates protein kinase C through oxidative stress in breast cancer cells [194], Unfortunately, most breast cancers initially responsive to tamoxifen treatment later become resistant. Schiff et al. [195] suggested that the conversion of breast tumors to a tamoxifen-resistant phenotype is associated with oxidative stress and depends on significantly enhanced SOD activity in tumors. 

Both unsymmetrical diols and alkenes can be prepared by applying these methods to mixtures of two different carbonyl compounds. An excess of one component can be used to achieve a high conversion of the more valuable reactant. A mixed reductive deoxygenation using TiCl4/Zn has been used to prepare 4-hydroxytamoxifen, the active antiestrogenic metabolite of tamoxifen. 

In contrast to UGTlA-related irinotecan toxicity, where low enzyme activity results in prolonged exposure to a toxic metabolite, another common chemotherapeutic agent, tamoxifen, has received recent attention for the role of specific enzymes in conversion of this prodrug to its active metabolites. The second part of this article discusses the elfects of CYP variants on tamoxifen therapy. 

Should not be used concurrently with tamoxifen not indicated for premenopausal women or women with ER-negative tumors used in postmenopausal women because peripheral conversion of adrenal androgens to estrogens is the primary source of estrogen not used in premenopausal women because it does not interfere with production of ovarian estrogens... 

McCague, R., Parr, I.B. and Haynes, B.P. (1990) Metabolism of the 4-iodo derivative of tamoxifen by isolated rat hepatocytes. Demonstration that the iodine atom reduces metabolic conversion and identification of four metabolites. Biochemical Pharmacology, 40,2277-2283. 

In 6 menopausal women with breast cancer aminoglutethimide 250 mg four times daily for 6 weeks markedly reduced the serum levels of tamoxifen 20 to 80 mg daily and most of its metabolites. The clearance of the tamoxifen was inereased by 3.2-fold and the tamoxifen AUC was re-dueed by 73% (range 56 to 80%). Conversely, the concurrent use of anastrozole 1 mg daily for 28 days did not affect the pharmacokinetics of tamoxifen in a double-blind, placebo-controlled study in 34 women with breast eaneer who had been taking tamoxifen 20 mg daily for at least 10 weeks. Similarly, letrozole 2.5 mg daily had no effeet on the pharma-eokineties of tamoxifen in 18 women taking tamoxifen 20 mg daily. Further, a study in 32 women clinically disease-free following primary treatment for breast eaneer and who had been taking tamoxifen 20 mg daily for at least 4 months found that exemestane 25 mg daily for 8 weeks... 

Propose reagents for the conversion of A to tamoxifen. Note The final step in this synthesis gives a mixture of E and Z isomers. 

Tamoxifen is the most widely used anti-oestrogen for the treatment of hormone-dependent breast cancer. The specific drug is used as a hormonal therapy for patients who exhibit ER+ breast cancer. The pharmacological activity of tamoxifen depends on its conversion to its active metabolite, endoxifen, by CYP2D6. Mechanisms of action and side effects have been recently revised [34 ]. 

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