Lv Wei, Liu Jinzhong, Skaar Todd C, Flockhart David A, Cushman Mark
†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.
‡Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, Indiana 46202, United States.
J Med Chem. 2015 Mar 26;58(6):2623-48. doi: 10.1021/jm501218e. Epub 2015 Mar 9.
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.
选择性雌激素受体调节剂和芳香化酶抑制剂都被广泛用于治疗乳腺癌。具有芳香化酶抑制和雌激素受体调节双重活性的化合物在乳腺癌治疗中可能具有特殊优势。我们之前的研究发现了去甲恩杂二酚，它是首个具有芳香化酶抑制和雌激素受体结合双重活性的化合物。为了优化其疗效以及相对于其他细胞色素P450酶的芳香化酶选择性，我们设计并合成了一系列结构相关的去甲恩杂二酚类似物。与去甲恩杂二酚相比，最有效的化合物4'-羟基去甲恩杂二酚（10）对芳香化酶的抑制效力更高，对雌激素受体的亲和力更强。10对芳香化酶相对于其他细胞色素P450酶的选择性也优于去甲恩杂二酚。因此，4'-羟基去甲恩杂二酚是一个有趣的先导化合物，可进一步开发以获得对乳腺癌治疗具有潜在价值的新型抗癌药物。
