Structural optimization of 10-methyl-aplog-1, a simplified analog of debromoaplysiatoxin, as an anticancer lead
Structural optimization of 10-methyl-aplog-1, a simplified analog of debromoaplysiatoxin, as an anticancer lead
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DOI：
10.1080/09168451.2015.1091718
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发表时间：
2016-02-01
影响因子：
1.6
通讯作者：
Irie, Kazuhiro
中科院分区：
文献类型：
--
作者：
Kikumori, Masayuki;Yanagita, Ryo C.;Irie, Kazuhiro
Aplog-1是一种简化的脱溴阿糖腺苷（DAT）类似物，具有强效的促肿瘤和促炎活性。Aplog-1和DAT对几种人类癌细胞系表现出抗增殖活性，而Aplog-1不具有促肿瘤或促炎活性。我们最近发现10-甲基-aplog-1（1）与aplog-1相比具有强的抗增殖活性。为了进一步研究参与肿瘤促进、促炎和抗增殖活性的结构因子，合成了aplog-1的两个二甲基衍生物（2，3），其中两个甲基安装在位置4和10或10和12。10，12-Dimethyl-aplog-1（2）对几种人类癌细胞系的生长具有比1和DAT更强的抑制作用，但没有显示出促肿瘤和促炎活性。相反，4，10-二甲基-aplog-1（3）显示出弱的促肿瘤和促炎活性，沿着与1和DAT类似的抗增殖活性。化合物2将是DAT的简化类似物中抗癌药物的最佳种子。
Aplog-1 is a simplified analog of debromoaplysiatoxin (DAT) with potent tumor-promoting and proinflammatory activities. Aplog-1 and DAT exhibited anti-proliferative activities against several human cancer cell lines, whereas aplog-1 did not have tumor-promoting nor proinflammatory activities. We have recently found 10-methyl-aplog-1 (1) to have strong anti-proliferative activity compared with aplog-1. To further investigate the structural factors involved in the tumor-promoting, proinflammatory, and anti-proliferative activities, two dimethyl derivatives of aplog-1 (2, 3) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (2) had stronger inhibitory effects on the growth of several human cancer cell lines than 1 and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (3) displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of 1 and DAT. Compound 2 would be the optimized seed for anticancer drugs among the simplified analogs of DAT.