Synthesis and structure-activity relationship of non-peptidic antagonists of neuropilin-1 receptor

Wang-Qing Liu; Valentino Megale; Lucia Borriello; Bertrand Leforban; Matthieu Montès; Elodie Goldwaser; Nohad Gresh; Jean-Philip Piquemal; Reda Hadj-Slimane; Olivier Hermine; Christiane Garbay; Françoise Raynaud; Yves Lepelletier; Luc Demange

doi:10.1016/j.bmcl.2014.07.028

Synthesis and structure-activity relationship of non-peptidic antagonists of neuropilin-1 receptor

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4254-9. doi: 10.1016/j.bmcl.2014.07.028. Epub 2014 Jul 17.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ Conservatoire National des Arts et Métiers, Chaire de Bioinformatique, Laboratoire Génomique, Bioinformatique et Applications, EA 4627, 292 rue Saint Martin, 75003 Paris, France.
⁶ 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.
⁷ 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.
⁸ Laboratoire de Chimie Théorique, Sorbonne Universités, UPMC, Paris 6, case courrier 137, 4, place Jussieu, 75252 Paris, France.
⁹ Tragex Pharma, 29 Rue Marcel Dassault, 92100 Boulogne-Billancourt, France.
¹⁰ 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.
¹¹ 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.
¹² 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.

PMID: 25091928
DOI: 10.1016/j.bmcl.2014.07.028

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.

Keywords: Angiogenesis; Docking to receptor; Heterocycles; Neuropilin; Protein–protein interaction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Adhesion / drug effects
Cell Line, Tumor
Dose-Response Relationship, Drug
Human Umbilical Vein Endothelial Cells / drug effects
Humans
Models, Molecular
Molecular Structure
Neuropilin-1 / antagonists & inhibitors*
Neuropilin-1 / metabolism
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-1 / metabolism

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Neuropilin-1
Vascular Endothelial Growth Factor Receptor-1