title: Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives.
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.
authors.affiliation: LIVE EA 4243, Université de la Nouvelle-Calédonie, avenue James Cook, BPR4, 98851 Nouméa, New Caledonia. Electronic address: thieury.c@live.fr.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Thieury
authors.affiliation: LIVE EA 4243, Université de la Nouvelle-Calédonie, avenue James Cook, BPR4, 98851 Nouméa, New Caledonia.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebouvier
authors.affiliation: UMS 3480 CNRS/US INSERM 018 BIOSIT Plateforme ImPACcell, Université de Rennes 1, 2 avenue du Pr Léon Bernard, 35043 Rennes Cedex, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Le Guével
authors.affiliation: 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.
authors.forename: Yann
authors.initials: Y
authors.lastname: Barguil
authors.affiliation: Spectropole, FR1739 - Faculté de Saint-Jérôme, Université d'Aix-Marseille, 52 Avenue Escadrille Normandie Niemen, 13013 Marseille, France.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Herbette
authors.affiliation: LIVE EA 4243, Université de la Nouvelle-Calédonie, avenue James Cook, BPR4, 98851 Nouméa, New Caledonia.
authors.forename: Cyril
authors.initials: C
authors.lastname: Antheaume
authors.affiliation: LIVE EA 4243, Université de la Nouvelle-Calédonie, avenue James Cook, BPR4, 98851 Nouméa, New Caledonia.
authors.forename: Edouard
authors.initials: E
authors.lastname: Hnawia
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Nishihamahoji-180 Yamashirocho, Tokushima 770-8514, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asakawa
authors.affiliation: LIVE EA 4243, Université de la Nouvelle-Calédonie, avenue James Cook, BPR4, 98851 Nouméa, New Caledonia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Nour
authors.affiliation: 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.
authors.forename: Thierry
authors.initials: T
authors.lastname: Guillaudeux
mesh_terms: D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002460:Cell Line; D045744:Cell Line, Tumor; D002599:Chalcone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D005419:Flavonoids; C500809:flavokawain A; C452039:flavokawain B; D002599:Chalcone
keywords: Akt/mTor; Apoptosis; Cancer; Cytotoxic; Flavokawain; P53; Structure activity relationships