title: Synthesis of non-prenyl analogues of baccharin as selective and potent inhibitors for aldo-keto reductase 1C3.
abstract: Inhibitors of a human member (AKR1C3) of the aldo-keto reductase superfamily are regarded as promising therapeutics for the treatment of prostatic and breast cancers. Baccharin [3-prenyl-4-(dihydrocinnamoyloxy)cinnamic acid], a component of propolis, was shown to be both potent (Ki 56 nM) and highly isoform-selective inhibitor of AKR1C3. In this study, a series of derivatives of baccharin were synthesized by replacing the 3-prenyl moiety with aryl and alkyl ether moieties, and their inhibitory activities for the enzyme were evaluated. Among them, two benzyl ether derivatives, 6m and 6n, showed an equivalent inhibitory potency to baccharin. The molecular docking of 6m in AKR1C3 has allowed the design and synthesis of (E)-3-{3-[(3-hydroxybenzyl)oxy]-4-[(3-phenylpropanoyl)oxy]phenyl}acrylic acid (14) with improved potency (Ki 6.4 nM) and selectivity comparable to baccharin. Additionally, 14 significantly decreased the cellular metabolism of androsterone and cytotoxic 4-oxo-2-nonenal by AKR1C3 at much lower concentrations than baccharin.
authors.affiliation: 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: Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan.
authors.forename: Dawei
authors.initials: D
authors.lastname: Hu
authors.affiliation: Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Otsuji
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia.
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.affiliation: Department of Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kandeel
authors.affiliation: Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
authors.affiliation: Department of Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: Department of Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kitade
authors.affiliation: Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan; Graduate School of Science and Technology for Research, University of Toyama, Toyama 930-8555, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Toyooka
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014255:Trichothecenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D014255:Trichothecenes; C012764:baccharin; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3
keywords: AKR1C3; Aldo-keto reductase; Baccharin; Cancer; Inhibitor; Selectivity