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

Cameron D. Buchman, Thomas Hurley

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Pages (from-to)2439-2455
Number of pages17
JournalJournal of Medicinal Chemistry
Volume60
Issue number6
DOIs
StatePublished - Mar 23 2017

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Ficusin
Coumarins
Aldehyde Dehydrogenase
Isoenzymes
Aldehydes
Pharmaceutical Chemistry
Carboxylic Acids
NAD
aldehyde dehydrogenase 1
Binding Sites
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives. / Buchman, Cameron D.; Hurley, Thomas.

In: Journal of Medicinal Chemistry, Vol. 60, No. 6, 23.03.2017, p. 2439-2455.

Research output: Contribution to journalArticle

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N2 - 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.

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