Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents
作者:Margherita Brindisi、Cristina Ulivieri、Gloria Alfano、Sandra Gemma、Francisco de Asís Balaguer、Tuhina Khan、Alessandro Grillo、Giulia Chemi、Grégory Menchon、Andrea E. Prota、Natacha Olieric、Daniel Lucena-Agell、Isabel Barasoain、J. Fernando Diaz、Angela Nebbioso、Mariarosaria Conte、Ludovica Lopresti、Stefania Magnano、Rebecca Amet、Paula Kinsella、Daniela M. Zisterer、Ola Ibrahim、Jeff O'Sullivan、Lucia Morbidelli、Roberta Spaccapelo、Cosima Baldari、Stefania Butini、Ettore Novellino、Giuseppe Campiani、Lucia Altucci、Michel O. Steinmetz、Simone Brogi
DOI:10.1016/j.ejmech.2018.11.004
日期:2019.1
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
微管靶向剂(MTA)是一类临床上成功的抗癌药物。对MTA的多药耐药性的出现要求开发具有多种机械性能的新型MTA。苯并a庚因最近被确定为一类新型的MTA。这些抗癌剂的抗肿瘤活性得到了彻底的表征,尽管它们的确切作用机理仍然难以捉摸。结合化学,生化,细胞,生物信息学和结构方面的努力,我们开发了改进的吡咯并萘并氧杂氮杂卓类抗肿瘤药,并阐明了它们在分子水平上的作用方式。化合物6jX射线证实它是最有效的类似物之一,是秋水仙碱的MTA。为了全面阐明结构-活性关系,进行了全面的结构研究。评价了选定的吡咯并萘并氧杂氮杂卓类化合物对多种癌细胞(包括耐多药细胞系)的细胞周期,凋亡和分化的影响。我们的结果将化合物6j定义为开发用于治疗耐药性肿瘤的有效化合物的潜在有用的最佳选择。