Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
J Med Chem. 2012 Oct 11;55(19):8464-76. doi: 10.1021/jm300930n. Epub 2012 Sep 24.
Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.
人细胞色素 P450 芳香酶以高度特异性催化雄激素合成雌激素。芳香酶抑制剂（AIs），如依西美坦、6-亚甲基雄甾-1,4-二烯-3,17-二酮，是治疗雌激素依赖性乳腺癌的卓越药物。人胎盘芳香酶的晶体结构显示出雄激素特异性的活性部位。通过利用结构数据，设计了新型 C6-取代的雄甾-1,4-二烯-3,17-二酮抑制剂。一些 C6-取代的 2-炔氧基化合物以纳摩尔范围内的 IC50 值抑制纯化的胎盘芳香酶。在 MCF-7 乳腺癌细胞系中的增殖研究表明，这些化合物中的一些具有 EC50 值优于 1 nM，超过了依西美坦。两种有效化合物的芳香酶复合物的 X 射线结构表明，根据其设计，新型侧基突出到酶-底物/依西美坦复合物未占据的进入通道开口中。观察到的结构-活性关系得到了 X 射线数据的证实。基于结构的设计允许利用芳香酶特异性相互作用来开发下一代 AIs。
