Synthesis, 3D-structure and stability analyses of NRPa-308, a new promising anti-cancer agent. Issue 24 (15th December 2019)

• Record Type: Journal Article
• Authors: Brachet, Etienne; Dumond, Aurore; Liu, Wang-Qing; Fabre, Marie; Selkti, Mohamed; Raynaud, Françoise; Hermine, Olivier; Benhida, Rachid; Belmont, Philippe; Garbay, Christiane; Lepelletier, Yves; Ronco, Cyril; Pagès, Gilles; Demange, Luc
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 24(2019)
• Publication Date: 2019-12-15
• Subjects: Anti-cancer agents -- Neuropilins -- NRPa-308 synthesis -- NRP-a308 stability; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.126710
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We report herein the synthesis of a newly described anti-cancer agent, NRPa-308. This compound antagonizes Neuropilin-1, a multi-partners transmembrane receptor overexpressed in numerous tumors, and thereby validated as promising target in oncology. The preparation of NRPa-308 proved challenging because of the orthogonality of the amide and sulphonamide bonds formation. Nevertheless, we succeeded a gram scale synthesis, according to an expeditious three steps route, without intermediate purification. This latter point is of utmost interest in reducing the ecologic impact and production costs in the perspective of further scale-up processes. The purity of NRPa-308 has been attested by means of conventional structural analyses and its crystallisation allowed a structural assessment by X-Ray diffraction. We also reported the remarkable chemical stability of this molecule in acidic, neutral and basic aqueous media. Eventually, we observed for the first time the accumulation of NRPa-308 in two types of human breast cancer cells MDA-MB231 and BT549.