Abstract
Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of debilitating disorders such as cancer, obesity, and inflammation. Drugs that can inhibit ALDH1a1 include disulfiram, an FDA-approved drug to treat chronic alcoholism. Disulfiram, by carbamylation of the catalytic cysteines, irreversibly inhibits ALDH1a1 and ALDH2. The latter is the isozyme responsible for important physiological processes such as the second stage of alcohol metabolism. Given the fact that ALDH1a1 has a larger substrate tunnel than that in ALDH2, replacing disulfiram ethyl groups with larger motifs will yield selective ALDH1a1 inhibitors. We report herein the synthesis of new inhibitors of ALDH1a1 where (hetero)aromatic rings were introduced into the structure of disulfiram. Most of the developed compounds retained the anti-ALDH1a1 activity of disulfiram; however, they were completely devoid of inhibitory activity against ALDH2.
Highlights
The aldehyde dehydrogenases (ALDHs) are a superfamily composed of 19 enzymes involved in a wide range of biological processes that are essential for cell survival and cell protection [1]
Overexpression of ALDH1a1 is associated with poor prognosis, tumor aggressiveness, and drug-resistance [8]
It was shown that disulfiram analogues in which the ethyl groups were replaced byaromatic rings preserved the entire inhibitory activity against ALDH1a1
Summary
The aldehyde dehydrogenases (ALDHs) are a superfamily composed of 19 enzymes involved in a wide range of biological processes that are essential for cell survival and cell protection [1]. The ALDH enzymes catalyze the metabolism of both endogenous and exogenous aldehydes [2] They are overexpressed in response to oxidative stress and lipid peroxidation [3]. Introducing the electrodonating methoxy group restored the activity of compound (4e), Molecules 2022, 27, 480 as it inhibits ALDH1a1 with an IC50 of 0.58 μM. This is in line with the fact that ALDH2 with its relatively small substrate tunnel cannot accommodate inhSibitors with bulk substituents [18]. To further confirm these findings, disulfiram aRndNits sSynSthesizNedRanalogue (2) were docked in silico into the active sites of both ALDH1a1 and ALDSH2, Figure 4.
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