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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Cryptolepine and aromathecin based mimics as potent G-quadruplex-binding, DNA-cleavage and anticancer agents: Design, synthesis and DNA targeting-induced apoptosis
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Cryptolepine and aromathecin based mimics as potent G-quadruplex-binding, DNA-cleavage and anticancer agents: Design, synthesis and DNA targeting-induced apoptosis

机译：Cryptolepine和Aromathecin基于有效的G-Quadruple-Briding，DNA - 切割和抗癌剂：设计，合成和DNA靶向诱导的细胞凋亡

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Thirty Cryptolepine and Aromathecin based mimics were designed and synthesized. Their cytotoxicity was evaluated in four human cancer cell lines (HepG-2, T24, NCI-H460 and MGC-803) and one normal human cell line (HL-7702). Most compounds exhibited potent anticancer activity with IC50 values from 0.31 to 11.97 mu M. 8-Fluoro-10-(N-3-dimethylaminopropyl)amino-11H-indeno[1,2-b]quinoline (5b) was identified as the most promising candidate in view of its anticancer activity. Molecular mechanism studies suggested that 5b not only could strongly bind to G-quadruplex, but intercalate into supercoil DNA and resulted in significant DNA double-strand break as well. Furthermore, 5b caused cell cycle arrest at S/G2 phase and induced apoptosis. After treatment with 5b, pro-apoptotic proteins Bak, Bax and Bim were up-regulated, anti-apoptotic proteins Bcl-2 and Bcl-xL were down-regulated, and the effector caspase-3/9 was activated to initiate apoptosis. The anticancer activity of 5b was finally validated in a MGC-803 xenograft tumor model with tumor growth inhibition (TGI) up to 53.2%, while displaying no obvious toxicity. Taken together, these results suggest that 5b may be a potential candidate of cytotoxic antineoplastic drugs for cancer therapy. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：设计和合成了三十个Cryptolepine和Aromathecin基础的模仿。它们在四种人癌细胞系（HepG-2，T24，NCI-H460和MGC-803）和一个正常人体细胞系（HL-7702）中评估它们的细胞毒性。大多数化合物用0.31至11.97μm的IC 50值表现出效率的抗癌活性.8-氟-10-（N-3-二甲基氨基丙基）氨基-11H-茚（1,2-B]喹啉（5B）是最多的鉴于其抗癌活动，候选人的候选人。分子机制研究表明，5B不仅可以强烈地结合G-Quadreple，而是嵌入超级燃料DNA并导致显着的DNA双链断裂。此外，5B在S / G2相导致细胞周期停滞并诱导细胞凋亡。在用5B处理后，上调促凋亡蛋白Bak，Bax和Bim，抗凋亡蛋白Bcl-2和Bcl-XL被下调，并激活效应胱天蛋白酶-3 / 9以引发细胞凋亡。最终在MgC-803异种移植肿瘤模型中验证了5B的抗癌活性，肿瘤生长抑制（TGI）高达53.2％，同时表现出明显的毒性。总之，这些结果表明，5B可以是癌症治疗的细胞毒性抗肿瘤药物的潜在候选者。 （c）2019年Elsevier Masson SAS。版权所有。

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