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 inhibitor daidzin for selectivity against
five ALDH1/2 isoenzymes. Compound 2 (Ki = 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
(Ki = 2.4 μM), and compound 32, which was 10-fold selective for ALDH1A1 (Ki = 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.