Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities.
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.
†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.
Wei
W
Lv
‡Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, Indiana 46202, United States.
Jinzhong
J
Liu
‡Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, Indiana 46202, United States.
Todd C
TC
Skaar
‡Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, Indiana 46202, United States.
David A
DA
Flockhart
†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.
Mark
M
Cushman
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D011960:Receptors, Estrogen / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; C574385:N,N-didesmethyl-4-hydroxytamoxifen; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System; D001141:Aromatase