5L2N

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

(2017) J Med Chem 60: 2439-2455

• PubMed: 28219011 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/acs.jmedchem.6b01825
• Primary Citation of Related Structures:  
  5L13, 5L2M, 5L2N, 5L2O


• PubMed Abstract: 
  

  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.

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Organizational Affiliation: 

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.