title: Synthesis and structure-activity relationship of non-peptidic antagonists of neuropilin-1 receptor.
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.
authors.affiliation: INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France.
authors.forename: Wang-Qing
authors.initials: WQ
authors.lastname: Liu
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France.
authors.forename: Valentino
authors.initials: V
authors.lastname: Megale
authors.affiliation: INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France; Tragex Pharma, 29 Rue Marcel Dassault, 92100 Boulogne-Billancourt, France.
authors.forename: Lucia
authors.initials: L
authors.lastname: Borriello
authors.affiliation: INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France; Tragex Pharma, 29 Rue Marcel Dassault, 92100 Boulogne-Billancourt, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leforban
authors.affiliation: Conservatoire National des Arts et Métiers, Chaire de Bioinformatique, Laboratoire Génomique, Bioinformatique et Applications, EA 4627, 292 rue Saint Martin, 75003 Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Montès
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France; Tragex Pharma, 29 Rue Marcel Dassault, 92100 Boulogne-Billancourt, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Goldwaser
authors.affiliation: INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France.
authors.forename: Nohad
authors.initials: N
authors.lastname: Gresh
authors.affiliation: Laboratoire de Chimie Théorique, Sorbonne Universités, UPMC, Paris 6, case courrier 137, 4, place Jussieu, 75252 Paris, France.
authors.forename: Jean-Philip
authors.initials: JP
authors.lastname: Piquemal
authors.affiliation: Tragex Pharma, 29 Rue Marcel Dassault, 92100 Boulogne-Billancourt, France.
authors.forename: Reda
authors.initials: R
authors.lastname: Hadj-Slimane
authors.affiliation: INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders, 24 Boulevard Montparnasse, 75015 Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, 24 boulevard Montparnasse, 75015 Paris, France; CNRS ERL 8254, 24 Boulevard Montparnasse, 75015 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.affiliation: INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Raynaud
authors.affiliation: INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders, 24 Boulevard Montparnasse, 75015 Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, 24 boulevard Montparnasse, 75015 Paris, France; CNRS ERL 8254, 24 Boulevard Montparnasse, 75015 Paris, France. Electronic address: y.lepelletier@gmail.com.
authors.forename: Yves
authors.initials: Y
authors.lastname: Lepelletier
authors.affiliation: INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France; Institut de Chimie de Nice (ICN), UMR 7272 CNRS, Université de Nice Sophia Antipolis, Parc Valrose, 06108 Nice cedex 1, France. Electronic address: luc.demange@parisdescartes.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Demange
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Angiogenesis; Docking to receptor; Heterocycles; Neuropilin; Protein–protein interaction