2. Academic Validation
  3. Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives

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

  • Bioorg Med Chem. 2017 Mar 15;25(6):1817-1829. doi: 10.1016/j.bmc.2017.01.049.
Charlotte Thieury 1,  Nicolas Lebouvier 2,  Rémy Le Guével 3,  Yann Barguil 4,  Gaëtan Herbette 5,  Cyril Antheaume 2,  Edouard Hnawia 2,  Yoshinori Asakawa 6,  Mohammed Nour 2,  Thierry Guillaudeux 7
Affiliations

Affiliations

  • 1 LIVE EA 4243, Université de la Nouvelle-Calédonie, avenue James Cook, BPR4, 98851 Nouméa, New Caledonia. Electronic address: thieury.c@live.fr.
  • 2 LIVE EA 4243, Université de la Nouvelle-Calédonie, avenue James Cook, BPR4, 98851 Nouméa, New Caledonia.
  • 3 UMS 3480 CNRS/US INSERM 018 BIOSIT Plateforme ImPACcell, Université de Rennes 1, 2 avenue du Pr Léon Bernard, 35043 Rennes Cedex, France.
  • 4 LIVE EA 4243, Université de la Nouvelle-Calédonie, avenue James Cook, BPR4, 98851 Nouméa, New Caledonia; Laboratoire de Biochimie et d'Hémostase, Hôpital Gaston Bourret, 7 avenue Paul Doumer, 98800 Nouméa, New Caledonia.
  • 5 Spectropole, FR1739 - Faculté de Saint-Jérôme, Université d'Aix-Marseille, 52 Avenue Escadrille Normandie Niemen, 13013 Marseille, France.
  • 6 Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Nishihamahoji-180 Yamashirocho, Tokushima 770-8514, Japan.
  • 7 UMS 3480 CNRS/US INSERM 018 BIOSIT Plateforme ImPACcell, Université de Rennes 1, 2 avenue du Pr Léon Bernard, 35043 Rennes Cedex, France; UMR INSERM U917 "Microenvironnement et cancer", Université de Rennes 1, 2 avenue du Pr Léon Bernard, 35043 Rennes Cedex, France; INSERM 440 Université de Rennes 1 "Oncogenesis Stress Signaling", Centre Eugène Marquis, 35043 Rennes Cedex, France.
PMID: 28214231 DOI: 10.1016/j.bmc.2017.01.049
Abstract

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; Apoptosis; Cancer; Cytotoxic; Flavokawain; P53; Structure activity relationships.

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