Discovery of a series of aromatic lactones as ALDH1/2-directed inhibitors

Cameron D. Buchman, Krishna K. Mahalingan, Thomas Hurley

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

In humans, the aldehyde dehydrogenase superfamily consists of 19 isoenzymes which mostly catalyze the NAD(P)<sup>+</sup>-dependent oxidation of aldehydes. Many of these isoenzymes have overlapping substrate specificities and therefore their potential physiological functions may overlap. Thus the development of new isoenzyme-selective probes would be able to better delineate the function of a single isoenzyme and its individual contribution to the metabolism of a particular substrate. This specific study was designed to find a novel modulator of ALDH2, a mitochondrial ALDH isoenzyme most well-known for its role in acetaldehyde oxidation. 53 compounds were initially identified to modulate the activity of ALDH2 by a high-throughput esterase screen from a library of 63,000 compounds. Of these initial 53 compounds, 12 were found to also modulate the oxidation of propionaldehyde by ALDH2. Single concentration measurements at 10 μM compound were performed using ALDH1A1, ALDH1A2, ALDH1A3, ALDH2, ALDH1B1, ALDH3A1, ALDH4A1, and/or ALDH5A1 to determine the selectivity of these 12 compounds toward ALDH2. Four of the twelve compounds shared an aromatic lactone structure and were found to be potent inhibitors of the ALDH1/2 isoenzymes, but have no inhibitory effect on ALDH3A1, ALDH4A1 or ALDH5A1. Two of the aromatic lactones show selectivity within the ALDH1/2 class, and one appears to be selective for ALDH2 compared to all other isoenzymes tested.

Original languageEnglish
Pages (from-to)38-44
Number of pages7
JournalChemico-Biological Interactions
Volume234
DOIs
StatePublished - Jun 5 2015

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Lactones
Isoenzymes
Oxidation
Aldehyde Dehydrogenase
Acetaldehyde
Substrates
Esterases
Substrate Specificity
aldehyde dehydrogenase 1
Metabolism
Aldehydes
NAD
Modulators
Throughput

Keywords

  • Aldehyde dehydrogenase
  • High-throughput screening
  • Inhibition

ASJC Scopus subject areas

  • Toxicology

Cite this

Discovery of a series of aromatic lactones as ALDH1/2-directed inhibitors. / Buchman, Cameron D.; Mahalingan, Krishna K.; Hurley, Thomas.

In: Chemico-Biological Interactions, Vol. 234, 05.06.2015, p. 38-44.

Research output: Contribution to journalArticle

Buchman, Cameron D. ; Mahalingan, Krishna K. ; Hurley, Thomas. / Discovery of a series of aromatic lactones as ALDH1/2-directed inhibitors. In: Chemico-Biological Interactions. 2015 ; Vol. 234. pp. 38-44.
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