title: Structure-activity relationship of human GLO I inhibitory natural flavonoids and their growth inhibitory effects.
abstract: Glyoxalase I (GLO I) is the rate-limiting enzyme for detoxification of methylglyoxal (MG), a side product of glycolysis, which is able to induce apoptosis. Since GLO I is known to be highly expressed in the most tumor cells and little in normal cells, specific inhibitors of this enzyme have been expected as effective anticancer drugs. The purpose of this study is a good construction of the human GLO I/inhibitor pharmacophore to obtain unique human GLO I inhibitory seed compounds for the development of useful anticancer drugs. Here, we selected natural flavonoid compounds that possess a plane configuration of cis C-4 ketone and C-5 hydroxy groups as the substrate (MG) transition-state mimetic structure. These compounds were examined the inhibitory abilities to human GLO I activity and analyzed their structure-activity relationships to determine an important pharmacophore of flavonoids for the human GLO I binding. Our results point to the contribution of hydroxy groups at the B ring of flavonoids to the effective inhibition of the human GLO I. Based on the binding mode of flavonoids, we constructed the human GLO I/inhibitor pharmacophore. This work delivers the first three-dimensional (3D) structural data and explains certain flavonoids interact specifically with the human GLO I.
authors.affiliation: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takasawa
authors.forename: Saki
authors.initials: S
authors.lastname: Takahashi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Saeki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sunaga
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yoshimori
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Tanuma
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D007659:Ketones / Q000737:chemistry; D007791:Lactoylglutathione Lyase / Q000378:metabolism*; D015394:Molecular Structure; D018411:Spodoptera; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007659:Ketones; D007791:Lactoylglutathione Lyase