Synthesis and investigation of conformationally restricted analogues of lavendustin A as cytotoxic inhibitors of tubulin polymerization
Synthesis and investigation of conformationally restricted analogues of lavendustin A as cytotoxic inhibitors of tubulin polymerization
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DOI：
10.1021/jm0202270
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发表时间：
2002-10-10
影响因子：
7.3
通讯作者：
Cushman, M
中科院分区：
文献类型：
--
作者：
Mu, FR;Lee, DJ;Cushman, M
合成了一系列构象限制的类似物，以阐明不同酰胺构象的lavaustin A衍生物对癌细胞培养物的细胞毒性和抑制微管蛋白聚合的可能影响。构象受限的类似物是基于恶嗪二酮和异吲哚酮环系统。此外，酰胺键被顺式和反式烯烃部分替代。令人惊讶的是，结果表明构象的影响非常小。限制生物活性。由于所有合成的化合物具有与微管蛋白聚合抑制剂相似的细胞毒性和效力，因此苯胺环系统上存在的侧链在lavendustins的生物学效应中似乎并不重要。与苯胺环周围的结构相比，蓝曲霉素A的氢醌环可能是生物活性的更重要的决定因素。
A series of conformationally restricted analogues were synthesized in order to elucidate the possible effects of different amide conformations of lavendustin A derivatives on cytotoxicity in cancer cell cultures and on inhibition of tubulin polymerization. The conformationally restricted analogues were based on the oxazinedione and isoindolone ring systems. In addition, the amide bond was replaced by both cis and trans alkene moieties. Surprisingly, the results indicated very little effect of conformational. restriction on biological activity. Because all of the compounds synthesized had similar cytotoxicities and potencies as tubulin polymerization inhibitors, the side chain present on the aniline ring system does not appear to be important in the biological effects of the lavendustins. The hydroquinone ring of lavendustin A may be a more important determinant of the biological activity than the structure surrounding the aniline ring.