Conformation–activity relationship on novel 4-pyridylmethylthio derivatives with antiangiogenic activity

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• 作者：Takahiro Honda ; Hisashi Tajima ; Yasushi Kaneko ; Masakazu Ban ; Takaaki Inaba ; Yuriko Takeno ; Kazuyoshi Okamoto ; Hiroyuki Aono
• 关键词：4-Pyridylmethylthio derivative ; VEGF receptor2 tyrosine kinase ; A nonbonded intramolecular interaction
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 May 2008
• 卷：18
• 期：9
• 页码：2939-2943
• 文件大小：211 K

摘要

We found 4-pyridylmethylthio derivative 1 to be very effective in using antiangiogenesis activity to prevent proliferation of HUVECs (Human Umbilical Vein Endothelial Cells), which was induced by vascular endothelial growth factor (VEGF). Compound 1 was equally effective in inhibiting VEGF receptor2 tyrosine kinase (KDR, IC₅₀ = 26 nM). We deduced that the inhibition was the result of binding the catalytic domain of VEGF receptor2 tyrosine kinase in a similar fashion to both phthalazine derivative PTK787 2 and anthranylamide derivative AAL993 3. In this report, we will describe the conformational analyses, from ab initio MO calculation and X-ray crystallographic analyses, of compound 1 and the analogs, which include non-active 9, all in comparison with 2 and 3. The conformation–activity relationships suggest that a nonbonded intramolecular interaction between the sulfur and the carbonyl oxygen of 1 was very important in inhibiting KDR.