Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and The Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
Bioorg Med Chem. 2010 Jul 15;18(14):5352-66. doi: 10.1016/j.bmc.2010.05.042. Epub 2010 May 24.
A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC50 0.59 microM) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC50 70 nM) and 84 (IC50 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC50 of 80 microM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 microM and 0.27 microM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.
设计并合成了一系列新型白藜芦醇类似物，并评估了它们对芳香酶的抑制活性。利用人芳香酶（PDB 3eqm）的晶体结构，通过对接、分子力学能量最小化和计算机图形分子建模，对芳香酶抑制剂 32（IC50 为 0.59 μM）的作用机制进行了合理化解释，并利用这些信息设计了几种非常有效的抑制剂，包括化合物 82（IC50 为 70 nM）和 84（IC50 为 36 nM）。这些化合物的芳香酶抑制活性比先导化合物白藜芦醇（IC50 为 80 μM）要强得多。除了芳香酶抑制活性外，化合物 32 和 44 还显示出很强的 QR2 抑制活性（IC50 分别为 1.7 μM 和 0.27 μM），并且这两种化合物与 QR2 复合物的高分辨率 X 射线结构提供了对其 QR2 抑制机制的深入了解。这些研究产生的芳香酶和醌还原酶抑制剂在癌症的治疗和预防方面具有潜在价值。
