Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities

Journal of Medicinal Chemistry
Wei LvMark Cushman

Abstract

Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer.

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Citations

Aug 24, 2017·Chemistry & Biodiversity·Jianli MaDabei Tang
Jul 25, 2019·Expert Opinion on Drug Discovery·Angelo SpinelloAlessandra Magistrato
May 26, 2020·Archiv der Pharmazie·Rajeev KharbMohammad S Yar
Feb 24, 2018·Clinical Pharmacology and Therapeutics·Todd C Skaar, Zeruesenay Desta
Nov 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jessica CaciollaSilvia Gobbi

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