Synthesis and structure-activity relationship of non-peptidic antagonists of neuropilin-1 receptor.
Liu W,Megale V,Borriello L,Leforban B,Montès M,Goldwaser E,Gresh N,Piquemal J,Hadj-Slimane R,Hermine O,Garbay C,Raynaud F,Lepelletier Y,Demange L
Source :
2014 Jul 17
Pmid / DOI:
25091928
Abstract
Neuropilins (NRPs) are VEGF-A165 co-receptors over-expressed in tumor cells, and considered as targets in angiogenic-related pathologies. We previously identified compound 1, the first non-peptidic antagonist of the VEGF-A165/NRP binding, which exhibits in vivo anti-angiogenic and anti-tumor activities. We report here the synthesis and biological evaluations of new antagonists structurally-related to compound 1. Among these molecules, 4a, 4c and 4d show cytotoxic effects on HUVEC and MDA-MB-31 cells, and antagonize VEGF-A165/NRP-1 binding. This study confirmed our key structure-activity relationships hypothesis and paved the way to compound 1 'hit to lead' optimization.KEYWORDSAngiogenesis, Docking to receptor, Heterocycles, Neuropilin, Protein–protein interactionCopyright © 2014 Elsevier Ltd. All rights reserved.