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

Abstract 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, IC 50  = 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.