Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives

Charlotte Thieury (1) , Nicolas Lebouvier (1) , Rémy Le Guével (2) , Yann Barguil (3, 1) , Gaëtan Herbette (4) , Cyril Antheaume (1) , Edouard Hnawia (1) , Yoshinori Asakawa (5) , Mohammed Nour (1) , Thierry Guillaudeux (6, 7, 2, 8)

1 LIVE - Laboratoire Insulaire du Vivant et de l'Environnement
2 ImPACcell - Plate-forme ImPACcell
3 Centre Hospitalier Territorial de Noumea
4 AMU SPEC - Spectropôle - Aix Marseille Université
5 Tokushima Bunri University
6 MiCa - Microenvironnement et cancer
7 Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes
8 COSS - Chemistry, Oncogenesis, Stress and Signaling

22 Flavokawain derivatives (FKd) were obtained by one step syntheses in order to conduct a SAR study to understand the structural requirements for optimum and selective cytotoxicity. FKd and natural flavokawains A and B found into kava, a South Pacific traditional beverage, were evaluated against nine cancer and one healthy cell lines. The targeted cell cycle phases as well as the effects on the induction of apoptosis and cell cycle protein levels were investigated. Therapeutic improvements (more activity and selectivity) were achieved with FKd compared to natural flavokawains and notably with the 2',3,4',6'-tetramethoxychalcone (FKd 19). FKd induced a G1/S arrest on p53 wild-type cells and an M arrest on p53 mutant-type, via the up-regulation of p21 and cyclin B1 proteins, followed by apoptosis. Moreover, FKd exhibited a 24h-effect on Akt/mTor normal cells versus a 48h-effect on Akt/mTor up-regulated cells. The SAR study resulted in the conclusion that trimethoxy A-ring allowed the best compromise between cytotoxicity and selectivity, as well as the substitution of the meta position on the B-ring and the use of halogens substituents.

Keywords: Akt/mTor; p53; Flavokawain; Structure activity relationships; Apoptosis; Cancer; Cytotoxic

Domains: Chemical Sciences; Medicinal Chemistry; Life Sciences [q-bio]; Pharmaceutical sciences; Pharmacology; Life Sciences [q-bio]; Cancer

Charlotte Thieury, Nicolas Lebouvier, Rémy Le Guével, Yann Barguil, Gaëtan Herbette, et al.. Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives. Bioorganic and Medicinal Chemistry, 2017, 25 (6), pp.1817-1829. ⟨10.1016/j.bmc.2017.01.049⟩. ⟨hal-01485126⟩