title: Cinnamic acids as new inhibitors of 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3).
abstract: 17Beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) that is involved in the pre-receptor regulation of androgen and estrogen action in the human is an emerging therapeutic target in the treatment of hormone-dependent forms of cancer, such as prostate cancer, breast cancer and endometrial cancer. To discover novel inhibitors, we tested the effect of a series of cinnamic acids on the reductive activity of the human recombinant AKR1C3. The compounds were evaluated in a spectrophotometric assay using 9,10-phenanthrenequinone as a substrate. The best inhibitor in the series was alpha-methylcinnamic acid (IC50=6.4 microM). Also, unsubstituted cinnamic acid was a good inhibitor of AKR1C3 (IC50=50 microM). Small hydrophobic substituents of the phenyl ring did not alter the activity; however, substitution with polar groups decreased the potency of inhibition. The most active compounds in this series represent promising starting points for further structural modifications in the search for more potent inhibitors of AKR1C3.
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Petra
authors.initials: P
authors.lastname: Brozic
authors.forename: Barbara
authors.initials: B
authors.lastname: Golob
authors.forename: Natasa
authors.initials: N
authors.lastname: Gomboc
authors.forename: Tea Lanisnik
authors.initials: TL
authors.lastname: Rizner
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008689:Methacrylates / Q000737:chemistry / Q000494:pharmacology*; D010666:Phenylpropionates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002934:Cinnamates; D004791:Enzyme Inhibitors; D008689:Methacrylates; D010666:Phenylpropionates; C510582:alpha-methylcinnamic acid; C029010:cinnamic acid; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3