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Synthesis and biological evaluation of truncated α-tubulin-binding pironetin analogues lacking alkyl pendants in the side chain or the dihydropyrone ring

机译:截短的α-微管蛋白结合pironetin类似物的合成和生物学评价侧链或二氢吡喃环缺乏烷基垂饰

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摘要

The preparation of several new truncated analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the suppression of some of the alkyl pendants in either the side chain or the dihydropyrone ring. Their cytotoxic activity and their interactions with tubulin have been investigated. It has been found that all analogues are cytotoxic towards two either sensitive or resistant tumoral cell lines with similar IC50 values in each case, thus strongly suggesting that, like natural pironetin, they also display a covalent mechanism of action. Their cytotoxicity is, however, lower than that of the parent compound. This indicates that all alkyl pendants are necessary for the full biological activity, with the ethyl group at C-4 seemingly being particularly relevant. Most likely, the alkyl groups cause a restriction in the conformational mobility of the molecule and reduce the number of available conformations. This makes it more probable that the molecule preferentially adopts a shape which fits better into the binding point in α-tubulin.
机译:描述了天然二氢吡喃酮吡咯丁酮的几种新的截短的类似物的制备。它们与天然产物的区别主要在于抑制侧链或二氢吡喃酮环中的某些烷基侧基。已经研究了它们的细胞毒性活性及其与微管蛋白的相互作用。已经发现,所有类似物对每种情况下具有相似IC 50值的两种敏感或耐药肿瘤细胞系均具有细胞毒性,因此有力地表明,与天然吡咯丁酮一样,它们也显示出共价作用机制。然而,它们的细胞毒性低于母体化合物。这表明所有烷基侧基对于完整的生物活性都是必需的,C-4上的乙基似乎特别相关。烷基最有可能引起分子构象迁移率的限制并减少可用构象的数量。这使得该分子更有可能优先采用更适合α-微管蛋白的结合点的形状。

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