Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer.
Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer.
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DOI：
10.1016/j.bmc.2010.05.042
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发表时间：
2010-07-15
影响因子：
3.5
通讯作者：
Cushman, Mark
中科院分区：
文献类型：
--
作者：
Sun, Bin;Hoshino, Juma;Jermihov, Katie;Marler, Laura;Pezzuto, John M.;Mesecar, Andrew D.;Cushman, Mark
设计合成了一系列新的白藜芦醇类似物，并评价了它们对芳香酶的抑制活性。利用人芳香化酶（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学分子建模等方法，对芳香化酶抑制剂32 （IC50 0.59µM）的作用机制进行合理化，并利用这些信息设计出几种非常有效的抑制剂，包括化合物82 （IC50 70 nM）和84 （IC50 36 nM）。这些化合物的芳香酶抑制活性远高于先导化合物白藜芦醇，其IC50为80µM。除了芳香化酶抑制活性外，化合物32和44也表现出较强的QR2抑制活性（IC50分别为1.7µM和0.27µM），与这两种化合物复合物的QR2高分辨率x射线结构为其抑制QR2的机制提供了新的思路。由此产生的芳香化酶和醌还原酶抑制剂在治疗和预防癌症方面具有潜在的应用价值。
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 µM) 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 µM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 µM and 0.27 µM, 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.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.3
作者：
Gobbi, Silvia;Cavalli, Andrea;Bisi, Alessandra
通讯作者：
Bisi, Alessandra
影响因子：
3.6
作者：
Arvela, RK;Leadbeater, NE;Singer, RD
通讯作者：
Singer, RD
影响因子：
2.8
作者：
Alonso, Francisco;Riente, Paola;Yus, Miguel
通讯作者：
Yus, Miguel
影响因子：
8.8
作者：
Jamieson, D.;Tung, A. T. Y.;Boddy, A. V.
通讯作者：
Boddy, A. V.