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; Franҫoise 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

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, Franҫoise Raynaud, Yves Lepelletier, Luc Demange

Cancer Signaling and Microenvironment (CSM)

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29 Scopus citations

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.

Original language	English
Pages (from-to)	4254-4259
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2014.07.028
State	Published - Sep 1 2014

Keywords

Angiogenesis
Docking to receptor
Heterocycles
Neuropilin
Protein-protein interaction

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Liu, W. Q., Megale, V., Borriello, L., Leforban, B., Montès, M., Goldwaser, E., Gresh, N., Piquemal, J. P., Hadj-Slimane, R., Hermine, O., Garbay, C., Raynaud, F., Lepelletier, Y., & Demange, L. (2014). Synthesis and structure-activity relationship of non-peptidic antagonists of neuropilin-1 receptor. Bioorganic and Medicinal Chemistry Letters, 24(17), 4254-4259. https://doi.org/10.1016/j.bmcl.2014.07.028

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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.",

keywords = "Angiogenesis, Docking to receptor, Heterocycles, Neuropilin, Protein-protein interaction",

author = "Liu, {Wang Qing} and Valentino Megale and Lucia Borriello and Bertrand Leforban and Matthieu Mont{\`e}s and Elodie Goldwaser and Nohad Gresh and Piquemal, {Jean Philip} and Reda Hadj-Slimane and Olivier Hermine and Christiane Garbay and Franҫoise Raynaud and Yves Lepelletier and Luc Demange",

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Liu, WQ, Megale, V, Borriello, L, Leforban, B, Montès, M, Goldwaser, E, Gresh, N, Piquemal, JP, Hadj-Slimane, R, Hermine, O, Garbay, C, Raynaud, F, Lepelletier, Y & Demange, L 2014, 'Synthesis and structure-activity relationship of non-peptidic antagonists of neuropilin-1 receptor', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 17, pp. 4254-4259. https://doi.org/10.1016/j.bmcl.2014.07.028

TY - JOUR

T1 - Synthesis and structure-activity relationship of non-peptidic antagonists of neuropilin-1 receptor

AU - Liu, Wang Qing

AU - Megale, Valentino

AU - Borriello, Lucia

AU - Leforban, Bertrand

AU - Montès, Matthieu

AU - Goldwaser, Elodie

AU - Gresh, Nohad

AU - Piquemal, Jean Philip

AU - Hadj-Slimane, Reda

AU - Hermine, Olivier

AU - Garbay, Christiane

AU - Raynaud, Franҫoise

AU - Lepelletier, Yves

AU - Demange, Luc

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Docking to receptor

KW - Heterocycles

KW - Neuropilin

KW - Protein-protein interaction

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DO - 10.1016/j.bmcl.2014.07.028

M3 - Article

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SN - 0960-894X

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SP - 4254

EP - 4259

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

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ER -

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

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Keywords

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