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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis, antiproliferative activity and inhibition of tubulin polymerization by 1,5- and 1,8-disubstituted 10H-anthracen-9-ones bearing a 10-benzylidene or 10-(2-oxo-2-phenylethylidene) moiety.
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Synthesis, antiproliferative activity and inhibition of tubulin polymerization by 1,5- and 1,8-disubstituted 10H-anthracen-9-ones bearing a 10-benzylidene or 10-(2-oxo-2-phenylethylidene) moiety.

机译：带有10-亚苄基或10-（2-氧代-2-苯基亚乙基）部分的1,5-和1,8-二取代的10H-蒽-9-的合成，抗增殖活性和对微管蛋白聚合的抑制。

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摘要

A novel series of 1,5- and 1,8-disubstituted 10-benzylidene-10H-anthracen-9-ones and 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-ones was synthesized to assess the substituent effects on biological activity. The 3-hydroxy-2,4-dimethoxy-benzylidene analogue 16 h displayed strong antiproliferative activity against several tumor cell lines, including multi-drug resistant phenotypes. Flow cytometric studies showed that KB/HeLa cells treated by elected compounds were arrested in the G2/M phases of the cell cycle. Among the compounds tested for inhibition of tubulin polymerization, 14 compounds proved to be exceptionally active with IC(50) values < 1 microM. In the 1,5-dichloro-derived series of benzylideneanthracenones, E/Z isomers were separated and biological effects were monitored. We found that the olefinic geometry had no significant effect on biological activity. Furthermore, the E isomeric 1,5-dichloro-substituted phenacylidenes entirely proved to be more potent inhibitors of tubulin polymerization than the recently described 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-ones. In conclusion, the present study improves understanding of the action of anthracenone-based tubulin polymerization inhibitors and contributes to the design of further potent anti-tubulin drugs.
机译：合成了一系列新的1,5-和1,8-二取代的10-亚苄基-10H-蒽-9-酮和10-（2-氧代-2-苯基亚乙基）-10H-蒽-9-酮来评估取代基对生物活性的影响。 3-羟基-2,4-二甲氧基-亚苄基类似物16 h对几种肿瘤细胞系（包括多药耐药表型）显示出强大的抗增殖活性。流式细胞术研究表明，经选择的化合物处理的KB / HeLa细胞被阻滞在细胞周期的G2 / M期。在测试抑制微管蛋白聚合的化合物中，有14种化合物被证明具有异常活性，IC（50）值<1 microM。在1,5-二氯衍生的系列亚苄基蒽酮中，分离出E / Z异构体并监测其生物学效应。我们发现烯烃的几何形状对生物活性没有显着影响。此外，与最近描述的10-（2-氧代-2-苯基亚乙基）-10H-蒽-9-酮相比，E异构体1,5-二氯-取代的苯乙叉完全被证明是微管蛋白聚合的更有效抑制剂。总之，本研究提高了对基于蒽醌的微管蛋白聚合抑制剂作用的理解，并有助于进一步设计有效的抗微管蛋白药物。

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