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

Autor: Yann Barguil, Yoshinori Asakawa, Cyril Antheaume, Mohammed Nour, Charlotte Thieury, Rémy Le Guével, Thierry Guillaudeux, Edouard Hnawia, Gaëtan Herbette, Nicolas Lebouvier
Přispěvatelé: Laboratoire Insulaire du Vivant et de l'Environnement (LIVE), Université de la Nouvelle-Calédonie (UNC), Plate-forme ImPACcell (ImPACcell), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Territorial de Noumea, Spectropôle - Aix Marseille Université (AMU SPEC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Tokushima Bunri University, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), ImPACcell platform of UMS Biosit, Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Jonchère, Laurent
Rok vydání: 2017
Předmět:
p53
0301 basic medicine
Spectrometry
Mass
Electrospray Ionization
Cytotoxic
[CHIM.THER] Chemical Sciences/Medicinal Chemistry
Proton Magnetic Resonance Spectroscopy
Clinical Biochemistry
Pharmaceutical Science
Apoptosis
[SDV.CAN]Life Sciences [q-bio]/Cancer
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
Pharmacology
Biochemistry
Cell Line
Structure-Activity Relationship
03 medical and health sciences
Chalcone
0302 clinical medicine
[SDV.CAN] Life Sciences [q-bio]/Cancer
Cell Line
Tumor
Drug Discovery
Humans
Cytotoxic T cell
Carbon-13 Magnetic Resonance Spectroscopy
Cytotoxicity
Cyclin B1
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Cancer
Flavonoids
Chemistry
Organic Chemistry
Akt/mTor
Cell cycle
3. Good health
030104 developmental biology
Cell culture
[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
030220 oncology & carcinogenesis
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Molecular Medicine
Drug Screening Assays
Antitumor
Flavokawain
Structure activity relationships
Zdroj: Bioorganic and Medicinal Chemistry
Bioorganic and Medicinal Chemistry, Elsevier, 2017, 25 (6), pp.1817-1829. ⟨10.1016/j.bmc.2017.01.049⟩
Bioorganic and Medicinal Chemistry, 2017, 25 (6), pp.1817-1829. ⟨10.1016/j.bmc.2017.01.049⟩
ISSN: 0968-0896
1464-3391
DOI: 10.1016/j.bmc.2017.01.049
Popis: International audience; 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.
Databáze: OpenAIRE
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