Zhao Li-Ming, Jin Hai-Shan, Liu Jinzhong, Skaar Todd C, Ipe Joseph, Lv Wei, 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, IN 47907, United States; School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, Jiangsu, China.
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, IN 46202, United States.
Bioorg Med Chem. 2016 Nov 1;24(21):5400-5409. doi: 10.1016/j.bmc.2016.08.064. Epub 2016 Aug 31.
The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) derivatives with dual aromatase inhibitory activity and estrogen receptor binding activity. In the present study, some of the structural features of the potent AI letrozole were incorporated into the lead compound (norendoxifen) to afford a series of new dual AI/SERM agents based on a symmetrical diphenylmethylene substructure that eliminates the problem of E,Z isomerization encountered with norendoxifen-based AI/SERMs. Compound 12d had good aromatase inhibitory activity (IC=62.2nM) while also exhibiting good binding activity to both ER-α (EC=72.1nM) and ER-β (EC=70.8nM). In addition, a new synthesis was devised for the preparation of norendoxifen and its analogues through a bis-Suzuki coupling strategy.
设计和合成双功能芳香酶抑制剂/选择性雌激素受体调节剂（AI/SERMs）是发现新型乳腺癌治疗药物的一种有吸引力的策略。先前的研究工作已制备出具有双功能芳香酶抑制活性和雌激素受体结合活性的去甲烯诺昔芬（4）衍生物。在本研究中，将强效AI来曲唑的一些结构特征引入先导化合物（去甲烯诺昔芬）中，以得到一系列基于对称二苯基亚甲基结构的新型双功能AI/SERM药物，该结构消除了基于去甲烯诺昔芬的AI/SERMs所遇到的E，Z异构化问题。化合物12d具有良好的芳香酶抑制活性（IC = 62.2nM），同时对雌激素受体α（EC = 72.1nM）和雌激素受体β（EC = 70.8nM）均表现出良好的结合活性。此外，还设计了一种通过双铃木偶联策略制备去甲烯诺昔芬及其类似物的新合成方法。
