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

Wei Lv; Jinzhong Liu; Todd C Skaar; David A Flockhart; Mark Cushman

doi:10.1021/jm501218e

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

J Med Chem. 2015 Mar 26;58(6):2623-48. doi: 10.1021/jm501218e. Epub 2015 Mar 9.

Authors

Wei Lv¹, Jinzhong Liu², Todd C Skaar², David A Flockhart², Mark Cushman¹

Affiliations

¹ †Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
² ‡Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, Indiana 46202, United States.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Aromatase / metabolism
Aromatase Inhibitors / chemical synthesis
Aromatase Inhibitors / chemistry*
Aromatase Inhibitors / pharmacology*
Breast Neoplasms / drug therapy
Breast Neoplasms / metabolism
Cytochrome P-450 Enzyme System / metabolism
Drug Design*
Humans
MCF-7 Cells
Models, Molecular
Receptors, Estrogen / metabolism
Selective Estrogen Receptor Modulators / chemical synthesis
Selective Estrogen Receptor Modulators / chemistry*
Selective Estrogen Receptor Modulators / pharmacology*
Signal Transduction / drug effects
Tamoxifen / analogs & derivatives*
Tamoxifen / chemical synthesis
Tamoxifen / chemistry
Tamoxifen / pharmacology

Substances

Antineoplastic Agents
Aromatase Inhibitors
N,N-didesmethyl-4-hydroxytamoxifen
Receptors, Estrogen
Selective Estrogen Receptor Modulators
Tamoxifen
Cytochrome P-450 Enzyme System
Aromatase

Grants and funding

P30 CA023168/CA/NCI NIH HHS/United States