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Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2017-11-06 , DOI: 10.1016/j.bmcl.2017.11.010
Allan M Prior 1 , Xufen Yu 1 , Eun-Jung Park 2 , Tamara P Kondratyuk 1 , Yan Lin 1 , John M Pezzuto 2 , Dianqing Sun 1
Affiliation  

In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group.



中文翻译:


用芳香酶和醌还原酶 1 测定合成 2-芳基吲哚衍生物的构效关系和对接研究



在我们不断发现抗癌和化学预防药物的过程中,合成了一系列 2-芳基吲哚衍生物,并针对芳香酶和醌还原酶 1 (QR1) 进行了评估。生物学评价显示,几种化合物(例如, 2d ,IC 50 = 1.61 μM; 21 ,IC 50 = 3.05 μM; 27 ,IC 50 = 3.34 μM)显示出芳香酶抑制活性,最大抑制浓度(IC 50 )值的一半。低微摩尔浓度。就 QR1 诱导活性而言, 11 种表现出最高的 QR1 诱导率 (IR),但浓度双倍活性 (CD) 值较低(IR = 8.34,CD = 2.75 μM),而7 种表现出最强的 CD 值,为 1.12微米。双重作用化合物24显示出芳香酶抑制 (IC 50 = 9.00 μM) 以及 QR1 诱导 (CD = 5.76 μM) 活性。使用 CDOCKER (Discovery Studio 3.5) 进行的计算对接研究提供了有关芳香酶活性位点内 2-芳基吲哚的潜在结合模式的见解。主要是,2-芳基吲哚优选与2-芳基基团朝向活性位点内的小疏水袋结合。吲哚上的C-5吸电子基团被预测具有重要作用并与Ser478(OH)形成氢键。或者,吡啶基类似物可以与与血红素基团配位的吡啶基3'-氮取向。

更新日期:2017-11-06
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