Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
J Med Chem. 2011 Jun 23;54(12):4247-63. doi: 10.1021/jm200436t. Epub 2011 May 26.
A total of 53 N-benzoylated phenoxazines and phenothiazines, including their S-oxidized analogues, were synthesized and evaluated for antiproliferative activity, interaction with tubulin, and cell cycle effects. Potent inhibitors of multiple cancer cell lines emerged with the 10-(4-methoxybenzoyl)-10H-phenoxazine-3-carbonitrile (33b, IC(50) values in the range of 2-15 nM) and the isovanillic analogue 33c. Seventeen compounds strongly inhibited tubulin polymerization with activities higher than or comparable to those of the reference compounds such as colchicine. Concentration-dependent flow cytometric studies revealed that inhibition of K562 cell growth was associated with an arrest in the G2/M phases of the cell cycle, indicative of mitotic blockade. Structure-activity relationship studies showed that best potencies were obtained with agents bearing a methoxy group placed para at the terminal phenyl ring and a 3-cyano group in the phenoxazine. A series of analogues highlight not only the phenoxazine but also the phenothiazine structural scaffold as valuable pharmacophores for potent tubulin polymerization inhibitors, worthy of further investigation.
共合成并评价了 53 种 N-苯甲酰基吩嗪和吩噻嗪及其 S-氧化类似物的抗增殖活性、与微管蛋白的相互作用和细胞周期效应。10-(4-甲氧基苯甲酰基)-10H-吩嗪-3-甲腈 (33b，IC50值在 2-15 nM 范围内) 和异香草醛类似物 33c 是具有多种癌细胞系抑制活性的有效抑制剂。17 种化合物强烈抑制微管蛋白聚合，其活性高于或可与秋水仙碱等参考化合物相媲美。浓度依赖性流式细胞术研究表明，抑制 K562 细胞生长与细胞周期 G2/M 期阻滞相关，表明有丝分裂阻断。构效关系研究表明，在末端苯环对位带有甲氧基和吩嗪中带有 3-氰基的试剂具有最佳的效力。一系列类似物不仅突出了吩嗪，而且还突出了吩噻嗪结构支架作为有效的微管蛋白聚合抑制剂的药效团，值得进一步研究。
