1. Academic Validation
  2. Discovery of simplified benzazole fragments derived from the marine benzosceptrin B as necroptosis inhibitors involving the receptor interacting protein Kinase-1

Discovery of simplified benzazole fragments derived from the marine benzosceptrin B as necroptosis inhibitors involving the receptor interacting protein Kinase-1

  • Eur J Med Chem. 2020 Sep 1;201:112337. doi: 10.1016/j.ejmech.2020.112337.
Mohamed Benchekroun 1 Ludmila Ermolenko 1 Minh Quan Tran 1 Agathe Vagneux 1 Hristo Nedev 1 Claire Delehouzé 2 Mohamed Souab 3 Blandine Baratte 3 Béatrice Josselin 3 Bogdan I Iorga 1 Sandrine Ruchaud 4 Stéphane Bach 5 Ali Al-Mourabit 6
Affiliations

Affiliations

  • 1 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, 91190, France.
  • 2 SeaBeLife Biotech, Place Georges Teissier, 29680, Roscoff, France; Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France.
  • 3 Sorbonne Université, CNRS, FR 2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, 29680, Roscoff, France.
  • 4 Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France.
  • 5 Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France; Sorbonne Université, CNRS, FR 2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, 29680, Roscoff, France. Electronic address: bach@sb-roscoff.fr.
  • 6 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, 91190, France. Electronic address: ali.almourabit@cnrs.fr.
Abstract

With the aim to develop new chemical tools based on simplified natural metabolites to help deciphering the molecular mechanism of Necroptosis, simplified benzazole fragments including 2-aminobenzimidazole and the 2-aminobenzothiazole analogs were prepared during the synthesis of the marine benzosceptrin B. Conpounds inhibiting the RIPK1 protein kinase were discovered. A library of 54 synthetic analogs were prepared and evaluated through a phenotypic screen using the inhibition of the necrotic cell death induced by TNF-α in human Jurkat T cells deficient for the FADD protein. This article reports the design, synthesis and biological evaluation of a series of 2-aminobenzazoles on the necroptotic cell death through the inhibition of RIPK1 protein kinase. The 2-aminobenzimidazole and 2-aminobenzothiazole platforms presented herein can serve as novel chemical tools to study the molecular regulation of Necroptosis and further develop lead drug candidates for chronic pathologies involving Necroptosis.

Keywords

Aminobenzimidazole; Kinase inhibitors; Necroptosis; Synthesis.

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