Synthesis and biological activity of fluorinated combretastatin analogues
Synthesis and biological activity of fluorinated combretastatin analogues
复制标题
DOI：
10.1021/jm701362m
复制
发表时间：
2008-05-08
影响因子：
7.3
通讯作者：
Pisano, Claudio
中科院分区：
文献类型：
--
作者：
Alloatti, Domenico;Giannini, Giuseppe;Pisano, Claudio
为了了解氟对考布他汀衍生物顺式二苯乙烯部分双键的影响，并受到初步分子模型研究显示与微管蛋白相互作用位点不同生物环境的鼓励，我们通过各种合成方法制备了一个小型化合物库，其中一个或两个烯属氢被氟取代。对二氟-CA-4 类似物的 X 射线分析表明，与非氟化对应物相比，该分子的空间排列没有改变。 SAR 分析证实了二苯乙烯支架顺式立体化学的重要性。然而，在一些反式氟化衍生物上观察到了一些意想不到的结果。双键上氟原子的位置可能影响这些化合物对微管蛋白聚合的抑制和细胞毒活性。
With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.