Modification of 3-arylisoquinolines into 3,4-diarylisoquinolines and assessment of their cytotoxicity and topoisomerase inhibition
Modification of 3-arylisoquinolines into 3,4-diarylisoquinolines and assessment of their cytotoxicity and topoisomerase inhibition
复制标题
DOI：
10.1016/j.ejmech.2015.01.016
复制
发表时间：
2015-03-06
影响因子：
6.7
通讯作者：
Cho, Won-Jea
中科院分区：
文献类型：
--
作者：
Khadka, Daulat Bikram;Woo, Hyunjung;Cho, Won-Jea
受单芳基异喹啉类化合物的初步成功和寻找更有效、选择性更强的具有拓扑异构酶(TOPO)抑制活性的抗癌药物的启发，设计并合成了一系列二芳基异喹啉类化合物(3，4-二芳基异喹诺酮类和3，4-二芳基异喹啉胺类)。这些化合物的合成主要包括锂基甲酰胺-苯甲腈的环加成反应、Suzuki偶联反应和亲核芳香取代反应。其中8个衍生物对人乳腺导管上皮肿瘤细胞(T47D)、人前列腺癌细胞(DU145)和人结肠腺癌细胞(HCT-15)有选择性毒性，但对正常人乳腺上皮细胞(MCF10A)没有影响。二芳基异喹啉类化合物的TOPO抑制活性与其化学结构密切相关。3，4-二芳基异喹诺酮类化合物一般对Topo I没有抑制作用，对Topo II只有中等的抑制作用。相反，几种3，4-二芳基异喹诺酮类化合物对Topo I的抑制活性较强。异喹啉胺衍生物对TOPO I的亲和力大于对TOPO II的亲和力。3，4-二芳基异喹啉类化合物对TOPO的抑制作用得到了对接模型的进一步支持，该对接模型显示了这些化合物与DNA/TOPO之间的插层和/或氢键作用(S)。对这些化合物的细胞毒性和TOPO抑制相关性的分析表明，具有较强细胞毒性的衍生物的主要生物靶点是TOPO，这反过来又确立了二芳基取代的异喹啉类化合物为一类新的潜在抗癌药物。(C)2015年爱思唯尔·马森公司。版权所有。
Inspired by the initial success of the monoarylisoquinolines and the quest to identify more potent and selective anticancer agents with topoisomerase (topo) inhibitory activity, series of diarylisoquinolines (3,4-diarylisoquinolones and 3,4-diarylisoquinolinamines) were designed and synthesized. Synthesis of these compounds primarily involved lithiated toluamide-benzonitrile cycloaddition, Suzuki coupling, and nucleophilic aromatic substitution reactions. Eight of the derivatives were selectively toxic against human ductal breast epithelial tumor cells (T47D), human prostate cancer cells (DU145), and human colorectal adenocarcinoma cells (HCT-15), but had no effect on normal human breast epithelial cells (MCF10A). The topo inhibitory activities of the diarylisoquinoline compounds were relatively dependent upon their chemical structure. 3,4-Diarylisoquinolones generally did not inhibit topo I and only showed moderate inhibition of topo II. In contrast, several 3,4-diarylisoquinolinamines showed superior topo I inhibitory activity. Isoquinolinamine derivatives had greater affinity for topo I than for topo II. Topo inhibition by 3,4-diarylisoquinolines was further supported by docking models showing intercalative and/or H-bond interactions between these compounds and the DNA/topo(s). An analysis of the correlation between the cytotoxicity and topo inhibition of these compounds indicated that the primary biological target of derivatives with potent cytotoxicity was topo, which in turn establishes diaryl-substituted isoquinolines as a novel class of potential anticancer drugs. (C) 2015 Elsevier Masson SAS. All rights reserved.