title: Structure-activity relationship of flavonoids as potent inhibitors of carbonyl reductase 1 (CBR1).
abstract: Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces a variety of carbonyl compounds including therapeutic drugs. CBR1 is involved in the reduction of the anthracycline anticancer drugs to their less anticancer C-13 hydroxy metabolites, which are cardiotoxic. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity, a side effect of the drugs. In this study, we evaluated 27 flavonoids for their inhibitory activities of CBR1 in order to explore the structure-activity relationship (SAR). Among them, luteolin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one) showed the most potent inhibition (IC5095nM), which is also more potent compared to all known classes of CBR1 inhibitors. The inhibition of luteolin was noncompetitive with respect to the substrate in the NADPH-dependent reduction direction, but CBR1 exhibited moderate NADP(+)-dependent dehydrogenase activity for some alicyclic alcohols, in which the luteolin inhibition was competitive with respect to the alcohol substrate (Ki59nM). The SAR of the flavonoids indicated that the 7-hydroxy group of luteolin was responsible for the potent inhibition of CBR1. The molecular docking of luteolin in CBR1-NADPH complex showed that theflavonoid binds to the substrate-binding cleft, in which its 7-hydroxy group formed a H-bond with main-chain oxygen of Met234, in addition to H-bond interactions (of its 5-hydroxy and 4-carbonyl groups with catalytically important residues Tyr193 and/or Ser139) and a π-stacking interaction (between its phenyl ring and Trp229).
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: sendo@gifu-pu.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Namiki
authors.initials: N
authors.lastname: Miyagi
authors.affiliation: Laboratory of Pharmacognosy, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Naohito
authors.initials: N
authors.lastname: Abe
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka 584-8540, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miura
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka 584-8540, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nishinaka
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka 584-8540, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Terada
authors.affiliation: Laboratory of Pharmacognosy, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Oyama
authors.affiliation: School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Goda
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.affiliation: Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D005419:Flavonoids / Q000737:chemistry*; D006801:Humans; D047311:Luteolin / Q000737:chemistry; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship
chemical_list: D005419:Flavonoids; D011994:Recombinant Proteins; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; D047311:Luteolin
keywords: (S)-(+)-1,2,3,4-Tetrahydro-1-naphthol (PubChem CID: 7058029); Acacetin (PubChem CID: 5280442); Apigenin (PubChem CID: 5280443); CBR1; Carbonyl reductase; Chrysin (PubChem CID: 5281607); Flavonoid; Isatin (PubChem CID: 7054); Kaempferide (PubChem CID: 5281666); Kaempferol (PubChem CID: 5280863); Luteolin; Luteolin (PubChem CID: 5280445); Quercetin (PubChem CID: 5280343); Quercitrin (PubChem CID: 5280459); Structure–activity relationship