Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives

Aldehyde dehydrogenase 2 (ALDH2), one of 19 ALDH superfamily members, catalyzes the NAD+-dependent oxidation of aldehydes to their respective carboxylic acids. In this study, we further characterized the inhibition of four psoralen and coumarin derivatives toward ALDH2 and compared them to the ALDH2...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2017-03, Vol.60 (6), p.2439-2455
Main Authors: Buchman, Cameron D, Hurley, Thomas D
Format: Article
Language:English
Subjects:
Aldehyde Dehydrogenase - antagonists & inhibitors
Aldehyde Dehydrogenase - chemistry
Aldehyde Dehydrogenase - metabolism
Aldehyde Dehydrogenase 1 Family
Aldehyde Dehydrogenase, Mitochondrial - antagonists & inhibitors
Aldehyde Dehydrogenase, Mitochondrial - metabolism
Coumarins - chemistry
Coumarins - pharmacology
Drug Design
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Ficusin - chemistry
Ficusin - pharmacology
Humans
Isoenzymes - antagonists & inhibitors
Isoenzymes - metabolism
Molecular Docking Simulation
Retinal Dehydrogenase - antagonists & inhibitors
Retinal Dehydrogenase - chemistry
Retinal Dehydrogenase - metabolism
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Summary:Aldehyde dehydrogenase 2 (ALDH2), one of 19 ALDH superfamily members, catalyzes the NAD+-dependent oxidation of aldehydes to their respective carboxylic acids. In this study, we further characterized the inhibition of four psoralen and coumarin derivatives toward ALDH2 and compared them to the ALDH2 inhibitor daidzin for selectivity against five ALDH1/2 isoenzymes. Compound 2 (K i = 19 nM) binds within the aldehyde-binding site of the free enzyme species of ALDH2. Thirty-three structural analogs were examined to develop a stronger SAR profile. Seven compounds maintained or improved upon the selectivity toward one of the five ALDH1/2 isoenzymes, including compound 36, a selective inhibitor for ALDH2 (K i = 2.4 μM), and compound 32, which was 10-fold selective for ALDH1A1 (K i = 1.2 μM) versus ALDH1A2. Further medicinal chemistry on the compounds’ basic scaffold could enhance the potency and selectivity for ALDH1A1 or ALDH2 and generate chemical probes to examine the unique and overlapping functions of the ALDH1/2 isoenzymes.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01825