Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents
Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents
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DOI：
10.1016/j.ejmech.2018.11.004
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发表时间：
2019-01-15
影响因子：
6.7
通讯作者：
Brogi, Simone
中科院分区：
文献类型：
--
作者：
Brindisi, Margherita;Ulivieri, Cristina;Brogi, Simone
微管靶向药物（mta）是一类临床成功的抗癌药物。多药耐药的出现要求开发具有多种机制特性的新型多药耐药药物。苯并恶西卓类药物最近被确定为一类新的mta。这些抗癌药物的抗肿瘤活性已被充分表征，但其确切的作用机制尚不清楚。结合化学、生化、细胞、生物信息学和结构等方面的努力，我们开发了改进的吡咯萘杂氮类抗肿瘤药物，并在分子水平上阐明了它们的作用方式。化合物6j是最有效的类似物之一，经x射线证实为秋水仙碱位点MTA。为了完整地阐明构效关系，进行了全面的结构研究。本研究评估了所选吡咯萘唑类药物对多种肿瘤细胞（包括多药耐药细胞系）的细胞周期、凋亡和分化的影响。我们的研究结果将化合物6j定义为一个潜在的有用的优化打击，用于开发治疗耐药肿瘤的有效化合物。(C) 2018 Elsevier Masson SAS。版权所有。
Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors. (C) 2018 Elsevier Masson SAS. All rights reserved.