Synthesis and Biological Activity of Fluorinated Combretastatin Analogues

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• 作者：Domenico Alloatti ; Giuseppe Giannini ; Walter Cabri ; Isabella Lustrati ; Mauro Marzi ; Andrea Ciacci ; Grazia Gallo ; M. Ornella Tinti ; Marcella Marcellini ; Teresa Riccioni ; Mario B. Guglielmi ; Paolo Carmi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：May 8, 2008
• 年：2008
• 卷：51
• 期：9
• 页码：2708 - 2721
• 全文大小：832K
• 年卷期：v.51,no.9(May 8, 2008)
• ISSN：1520-4804

文摘

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.