title: Design, Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors.
abstract: The recent discovery of c-Jun NH2-terminal kinase JNK1 suppression by natural quercetagetin (1) is a promising lead for the development of novel anticancer agents. Using both X-ray structure and docking analyses we predicted that 5'-hydroxy- (2) and 5'-hydroxymethyl-quercetagetin (3) would inhibit JNK1 more actively than the parent compound 1. Notably, our drug design was based on the active enzyme-ligand complex as opposed to the enzyme's relatively open apo structure. In this paper we test our theoretical predictions, aided by docking-model experiments, and report the first synthesis and biological evaluation of quercetagetin analogues 2 and 3. As calculated, both compounds strongly suppress JNK1 activity. The IC50 values were determined to be 3.4 μM and 12.2 μM, respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC50 =4.6 μM). Compound 2 was also shown to suppress matrix metalloproteinase-1 expression with high specificity after UV irradiation.
authors.affiliation: Institute for Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476.
authors.forename: Judith
authors.initials: J
authors.lastname: Hierold
authors.affiliation: Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried (Germany).|Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Republic of Korea).|Proteros Biostructures GmbH, Bunsenstr. 7a, 82152 Martinsried (Germany).
authors.forename: Sohee
authors.initials: S
authors.lastname: Baek
authors.affiliation: Institute for Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476.
authors.forename: Rene
authors.initials: R
authors.lastname: Rieger
authors.affiliation: Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Republic of Korea).
authors.forename: Tae-Gyu
authors.initials: TG
authors.lastname: Lim
authors.affiliation: Institute for Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476.
authors.forename: Saman
authors.initials: S
authors.lastname: Zakpur
authors.affiliation: Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried (Germany).
authors.forename: Marcelino
authors.initials: M
authors.lastname: Arciniega
authors.affiliation: Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Republic of Korea).|WCU Biomodulation Major, Center for Food and Bioconvergence, Department of Agricultural Biotechnology, Seoul National University, Seoul (Republic of Korea).
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried (Germany).|Department of Chemistry, Technical University of Munich, Lichtenbergstraße 4, 85748 Garching (Germany).|Center for Medical Biotechnology, University of Duisburg-Essen, 45117 Essen (Germany).|School of Biosciences, Cardiff University, Cardiff (Wales, UK).
authors.forename: Robert
authors.initials: R
authors.lastname: Huber
authors.affiliation: Institute for Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476. ltietze@gwdg.de.
authors.forename: Lutz F
authors.initials: LF
authors.lastname: Tietze
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001685:Biological Factors; D002867:Chromones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D047309:Flavones; D006801:Humans; D020128:Inhibitory Concentration 50; D048055:Mitogen-Activated Protein Kinase 8 / Q000737:chemistry* / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D001685:Biological Factors; D002867:Chromones; D047309:Flavones; D048055:Mitogen-Activated Protein Kinase 8; C079163:quercetagetin
keywords: JNK1; drug design; flavonoids; inhibitors; synthetic drugs