European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100, Siena, Italy; Istituto Toscano Tumori, University of Siena, via Aldo Moro 2, I-53100, Siena, Italy.
Istituto Toscano Tumori, University of Siena, via Aldo Moro 2, I-53100, Siena, Italy; Department of Life Sciences, via Aldo Moro 2, I-53100, Siena, Italy.
Eur J Med Chem. 2019 Jan 15;162:290-320. doi: 10.1016/j.ejmech.2018.11.004. Epub 2018 Nov 3.
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.
微管靶向剂（MTAs）是一类临床应用成功的抗癌药物。MTAs 的多药耐药性的出现，需要开发具有不同作用机制的新型 MTAs。苯并恶嗪类化合物最近被确定为一类新型的 MTAs。尽管这些抗癌药物的抗肿瘤活性已经得到了深入的研究，但它们的确切作用机制仍不清楚。我们通过化学、生化、细胞、生物信息学和结构等方面的综合研究，开发了改进的吡咯并萘恶嗪类抗肿瘤药物，并阐明了它们在分子水平上的作用机制。其中一个最有效的类似物 6j 通过 X 射线证实是秋水仙碱结合位点的 MTA。为了全面阐明构效关系，对其进行了全面的结构研究。选择了一些吡咯并萘恶嗪类化合物，评估它们在多种癌细胞（包括多药耐药细胞系）中的细胞周期、凋亡和分化作用。我们的研究结果将化合物 6j 定义为一种潜在有用的优化命中化合物，可用于开发治疗耐药性肿瘤的有效化合物。
