Main research theme

This research theme focuses on the chemistry related to the biology of several series of bioactive lipids, including sphingolipids and:
 
  • Polyacetylenic lipids, a large family of marine compounds. They are characterized by the presence along a linear skeleton of alkynylcarbinol fragments. This acetylenic motif is associated with their immunosuppressive, antifungal, antiparasitic and antitumor properties. The chemical exploration of the structural variation and the mode of action of these marine lipids opens new perspectives.

Research orientations and results highlights

Polyacetylenic lipids are approached according to two main tracks:
 
  • Novel chiral alkynylcarbinol bio-inspired cytotoxic pharmacophores
We have implemented (collaboration R. Chauvin/V. Maraval-LCC and S. Britton-IPBS) the first systematic chemistry-driven structure-activity relationships study in this series. A few key modifications of a reference natural compound have made possible to increase its cytotoxic activity by a factor of 1000, thanks notably to the extension of the dialkynylcarbinol pharmacophore by conjugation. In particular, an entirely new critical influence of the configuration of the carbinol center was observed.

To enhance their pharmacological potential, we have developed a new aromatic conjugate series. Thanks to a modular synthetic route, we have synthesized nearly 50 derivatives of this family by varying the geometry of the molecule, the nature of the lipophilic chain, the presence of substituents on the aromatic ring or its nature, by introducing various heterocycles. Very active derivatives metabolically protected by the presence of fluorinated substituents have been obtained giving rise to a patent application.
PACs
PACs
The approach has been adapted to the synthesis of clickable probes used in cell imaging by click in cellulo chemistry, as well as in chemoproteomics. This contributed to the discovery of their unique mode of action. These compounds which act as prodrugs (collaboration S. Britton-IPBS), are enantiospecifically oxidized by short chain dehydrogenases/reductases (SDR). The resulting dialkynyl ketones irreversibly inactivate various cellular proteins by addition to the side chains of cysteines and lysines. This leads to stress of the Endoplasmic Reticulum and blockage of the ubiquitin-proteasome system resulting in cell death by apoptotosis.
 
  • Novel bio-inspired alkynylcarbinol lipidic molecules with anti-mycobacterial activities
Using a similar approach, we have also conducted a study of the structure-activity relationships of falcarindiol, a bioactive lipid which exhibits modest anti-mycobacterial activity associated with significant cytotoxicity for mammalian cells (collaboration R. Chauvin/V. Bernardes-Génisson-LCC and H. Marrakchi-IPBS). We have thus been able to obtain compounds with a simpler structure presenting a highly attenuated cytotoxicity and an anti-mycobacterial activity of the order of that of antituberculous active principles.

Other collaborative works

  • DNA-PK PROTACs (PROteolysis TArgeting Chimeric molecule), a kinase essential to the repair of DNA Double-Strand Breaks: collaboration S. Britton-IPBS, financement Ligue Régionale contre le Cancer funding.
  • Dual mitonchodrial oxidative phosphorylation inhibitors targeting relapse-initiating cells in acute myeloid leukemia residual disease: collaboration J.-E. Sarry-CRCT, Cancéropole Grand Sud-Ouest funding.
  • Mycobacterial PPTases (PhosphoPantéthéinylTansférases) inhibitors as anti-infective agents: collaboration L. Mourey/L. Maveyraud-IPBS), ANR funding.

Recent publications

  • Natural and bioinspired lipidic alkynylcarbinols as leishmanicidal, antiplasmodial, trypanocidal, fungicidal, antibacterial, and antimycobacterial agents. Jon Bouvet, Valérie Maraval, Stéphanie Ballereau, Vania Bernardes-Génisson, Yves Génisson. J. Nat. Prod., 2024, 87, 2550–2566.
  • Phenyl diAlkynylCarbinols (PACs), a bioinspired series of synthetic antitumor acetylenic lipids. Margaux Bossuat, P.auline Rullière, Nadège Preuilh, Antonio Peixoto, Etienne Joly, Jean-Guillaume Gomez, Maroua Bourkhis, Frédéric Rodriguez, Fernanda Gonçalves, Isabelle Fabing, Hafida Gaspard, Vania Bernardes-Genisson, Valérie Maraval, Stéphanie Ballereau, Remi Chauvin, Sébastien Britton, Yves Génisson, J. Med. Chem. 2023, 66, 13918−13945.
  • SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species. Pascal Demange, Etienne Joly, Julien Marcoux, Patrick R. A. Zanon, Dymytrii Listunov, Pauline Rullière, Cécile Barthes, Céline Noirot, Jean-Baptiste Izquierdo, Alexandrine Rozié, Karen Pradines, Romain Hee, Maria Vieira de Brito, Marlène Marcellin, Remy-Felix Serre, Olivier Bouchez, Odile Burlet-Schiltz, Maria C. F. Oliveira, Stéphanie Ballereau, Vania Bernardes-Génisson, Valérie Maraval, Patrick Calsou, Stephan M. Hacker, Yves Génisson, Remi Chauvin, Sébastien Britton. eLife 2022, 11:e73913.
  • Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds. Coralie Carivenc, Laurent Maveyraud, Claire Blanger, Stéphanie Ballereau, Coralie Roy-Camille, Minh Chau Nguyen, Yves Génisson, Christophe Guilhot, Christian Chalut, Jean-Denis Pedelacq, Lionel Mourey. Scientific Reports 2021, 11:18042.