Synthesis and structure–activity relationship of non-peptidic antagonists of neuropilin-1 receptor |
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| Institution: | 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. Tragex Pharma, 29 Rue Marcel Dassault, 92100 Boulogne-Billancourt, France;4. Conservatoire National des Arts et Métiers, Chaire de Bioinformatique, Laboratoire Génomique, Bioinformatique et Applications, EA 4627, 292 rue Saint Martin, 75003 Paris, France;5. Laboratoire de Chimie Théorique, Sorbonne Universités, UPMC, Paris 6, case courrier 137, 4, place Jussieu, 75252 Paris, France;6. INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders, 24 Boulevard Montparnasse, 75015 Paris, France;7. Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, 24 boulevard Montparnasse, 75015 Paris, France;8. CNRS ERL 8254, 24 Boulevard Montparnasse, 75015 Paris, France;9. Institut de Chimie de Nice (ICN), UMR 7272 CNRS, Université de Nice Sophia Antipolis, Parc Valrose, 06108 Nice cedex 1, France;1. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany;2. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany;1. Institut für Anorganische und Analytische Chemie, Friedrich-Schiller-Universität Jena, Humboldtstrasse 8, 07743 Jena, Germany;2. Department of Chemistry, Faculty of Sciences, University of Ibadan, Ibadan, Nigeria;3. Department of Chemical Sciences, Redeemer’s University, Ede, Osun State, Nigeria;1. Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;2. Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai 200237, China |
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| 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. |
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| Keywords: | Angiogenesis Neuropilin Protein–protein interaction Docking to receptor Heterocycles |
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