Wu Lan, Bao Kai, Song Rui, Wang Defa, Zhang Lei, Wang Weiyun, Zhang Weige, Bin Wen
Department of Geratology, The First Affiliated Hospital of Chinese Medical University, Shenyang, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
PLoS One. 2016 Jul 22;11(7):e0159503. doi: 10.1371/journal.pone.0159503. eCollection 2016.
In our continuing structure-activity relationship study of a new class of erythromycin A (EM-A) derivatives with antiproliferative activity, a new series of de(N-methyl) EM-A dimers jointed by a four-atom linker, -CH2CH = CHCH2-, were prepared and their antiproliferative activity against three human tumor cell lines was evaluated by MTT assay. The most active EM-A dimer, compound 1b, that carrying C6 methoxyl groups was further investigated and showed potent antiproliferative activity in six other human tumor cell lines. Flow cytometry analysis of 1b treated HeLa and MCF-7 cells indicated that the four-atom EM-A dimers induced the SubG1 phase cell cycle arrest and cell apoptosis, in time- and dose-dependent manners. Further experiments including morphologic observation, DNA agarose gel electrophoresis, mitochondrial potential alternation and western blot analysis revealed that the antiproliferative mechanism may involve the induction of apoptosis in activating the mitochondrial pathway, and regulation of apoptotic proteins.
在我们对一类具有抗增殖活性的新型红霉素A（EM-A）衍生物进行的持续构效关系研究中，制备了一系列由四原子连接基-CH2CH = CHCH2-连接的脱（N-甲基）EM-A二聚体，并通过MTT法评估了它们对三种人类肿瘤细胞系的抗增殖活性。对活性最高的带有C6甲氧基的EM-A二聚体化合物1b进行了进一步研究，结果显示其在其他六种人类肿瘤细胞系中也具有强大的抗增殖活性。对用1b处理的HeLa和MCF-7细胞进行的流式细胞术分析表明，四原子EM-A二聚体以时间和剂量依赖性方式诱导亚G1期细胞周期停滞和细胞凋亡。包括形态学观察、DNA琼脂糖凝胶电泳、线粒体电位变化和蛋白质印迹分析在内的进一步实验表明，其抗增殖机制可能涉及激活线粒体途径诱导细胞凋亡以及对凋亡蛋白的调节。
