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Article Dans Une Revue Bioorganic and Medicinal Chemistry Letters Année : 2019

Synthesis, 3D-structure and stability analyses of NRPa-308, a new promising anti-cancer agent

Résumé

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 ortho-gonality 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. Tumor neoangiogenesis supplies cancer cells in oxygen and nutrients. Moreover, the neoformed blood vessels promote also the dissemination of malignant cells to healthy tissues. Therefore, tackling angiogenesis proved to be a relevant therapeutic option in oncology since more than 30 years.
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Dates et versions

hal-02418648 , version 1 (19-12-2019)

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Etienne Brachet, Aurore Dumond, Wang-Qing Liu, Marie Fabre, Mohamed Selkti, et al.. Synthesis, 3D-structure and stability analyses of NRPa-308, a new promising anti-cancer agent. Bioorganic and Medicinal Chemistry Letters, 2019, 29 (24), pp.126710. ⟨10.1016/j.bmcl.2019.126710⟩. ⟨hal-02418648⟩
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