Osthenol, a prenylated coumarin, as a monoamine oxidase A inhibitor with high selectivity. Issue 6 (15th March 2019)

• Record Type: Journal Article
• Authors: Baek, Seung Cheol; Kang, Myung-Gyun; Park, Ji-Eun; Lee, Jae Pil; Lee, Hanna; Ryu, Hyung Won; Park, Chul Min; Park, Daeui; Cho, Myoung-Lae; Oh, Sei-Ryang; Kim, Hoon
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 6(2019)
• Page Start: 839
• Page End: 843
• Publication Date: 2019-03-15
• Subjects: Osthenol -- Human monoamine oxidase A -- Selective competitive inhibitor -- Molecular docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.01.016
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Osthenol was a potent (IC50 = 0.74 µM) and selective inhibitor for hMAO-A (SI > 81.1). Osthenol was a reversible and competitive inhibitor (Ki = 0.26 µM). The binding affinity of osthenol for hMAO-A was greater than that for hMAO-B. The 8-(3, 3-dimethylallyl) group of osthenol increased its inhibitory activity against hMAO-A. Osthenol can be a potential lead compound for design of novel reversible MAO-A inhibitors. Abstract: Osthenol (6 ), a prenylated coumarin isolated from the dried roots of Angelica pubescens, potently and selectively inhibited recombinant human monoamine oxidase-A (hMAO-A) with an IC50 value of 0.74 µM and showed a high selectivity index (SI > 81.1) for hMAO-A versus hMAO-B. Compound6 was a reversible competitive hMAO-A inhibitor (Ki = 0.26 µM) with a potency greater than toloxatone (IC50 = 0.93 µM), a marketed drug. Isopsoralen (3 ) and bakuchicin (1 ), furanocoumarin derivatives isolated from Psoralea corylifolia L., showed slightly higher IC50 values (0.88 and 1.78 µM, respectively) for hMAO-A than6, but had low SI values (3.1 for both). Other coumarins tested did not effectively inhibit hMAO-A or hMAO-B. A structural comparison suggested that the 8-(3, 3-dimethylallyl) group of6 increased its inhibitory activity against hMAO-A compared with the 6-methoxy group of scopoletin (4 ). Molecular docking simulations revealed that the binding affinity of6 for hMAO-A (−8.5 kcal/mol) was greater than that for hMAO-B (−5.6 kcal/mol) and that of4 for hMAO-A (−7.3 kcal/mol). Docking simulations also implied that6 interacted with hMAO-A at Phe208 and with hMAO-B at Ile199 by carbon hydrogen bondings. Our findings suggest that osthenol, derived from natural products, is a selective and potent reversible inhibitor of MAO-A, and can be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors.