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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >5-Chlorobenzofuran-2-carboxamides: From allosteric CB1 modulators to potential apoptotic antitumor agents
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5-Chlorobenzofuran-2-carboxamides: From allosteric CB1 modulators to potential apoptotic antitumor agents

机译：5-氯苯脲-2-甲酰胺：从变构CB1调节剂到潜在的凋亡抗肿瘤剂

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摘要

Cannabinoids as THC and the CB1 allosteric modulator CBD were reported to have antiproliferative activities with no reports for other CB1 allosteric modulators as the 5-chloroindole-2-carboxamide derivatives and their furan congeners. Based on the antiproliferative activity of two 5-chlorobenzofuran-2-carboxamide allosteric CB1 modulators, a series of novel derivatives was designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 mu M. Some derivatives showed good antiproliferative activities against tumor cells as compounds 8,15, 21 and 22. The most active compound 15 showed equipotent activity to doxorubicin. Compounds 7, 9, 15, 16, 21 and 22 increased the level of active caspase 3 by 4-8 folds, compared to the control cells in MCF-7 cell line and doxorubicin as a reference drug. Compounds 15 and 21, the most activecaspase-3 inducers, increase the levels of caspase 8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of Cytochrome C levels in MCF-7 cell lines. Compound 15 exhibited cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of MCF-7 cell line. The drug Likeness profile of the synthesized compounds showed that all the compounds were predicted to have high oral absorption complying with different pharmacokinetics filters. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：据报道，大麻素作为THC和CB1变构调制剂CBD具有抗增殖活动，没有报告其他CB1变构调节剂作为5-氯吲哚-2-甲酰胺衍生物及其呋喃同一剂。基于两个5-氯苯并呋喃-2-甲酰胺的变构调节剂CB1的抗增殖活性，一系列新的衍生物的设计和合成。使用人乳腺上皮细胞系（MCF-10A）在细胞活力测定中测试合成的化合物，其中所有化合物没有表现出细胞毒性效应，并且以50μmm的浓度显示出超过85％的细胞活力。一些衍生物显示出良好的抗增殖性对肿瘤细胞的活性作为化合物8,15,21和22.最活性化合物15显示给多柔比星的等化活性。与MCF-7细胞系和多柔比蛋白的对照细胞相比，化合物7,9,15,16,21和22增加了4-8倍的活性胱天蛋酶3的水平。化合物15和21，最敏感的酶-3诱导剂，增加了Caspase 8和9的水平，表明患有内在和外在途径的活化，并显示出挥霍，下调Bcl-2蛋白水平和细胞色素的过度表达的效率诱导和过度表达C级别MCF-7细胞系。化合物15在MCF-7细胞系的细胞循环分析中表现出在G1和G2 / M阶段的细胞周期停滞。合成化合物的药物象征显示，预测所有化合物具有符合不同的药代动力学过滤器的高口气吸收。 （c）2019年Elsevier Masson SAS。版权所有。

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