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

Bioorganic & Medicinal Chemistry Letters
Takahiro HondaHiroyuki Aono

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)=26nM). 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.

References

Feb 7, 2002·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Yoshimitsu Nagao
Jun 1, 2005·Expert Opinion on Therapeutic Patents·Jacques Dumas, Julie A Dixon

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Citations

Dec 26, 2008·Bioorganic & Medicinal Chemistry·Takahiro HondaMasakazu Ban
Dec 7, 2013·Chemistry : a European Journal·Takuya NakashimaTsuyoshi Kawai
Dec 4, 2014·Bioorganic & Medicinal Chemistry Letters·Benjamin P FauberAihe Zhou
Jul 24, 2021·Organic Letters·Edwin Alfonzo, Sudhir M Hande
Mar 14, 2014·Journal of Medicinal Chemistry·Makonen BelemaNicholas A Meanwell

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