1. Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors.
- Author
-
Omran Z
- Subjects
- Acetaldehyde Dehydrogenase Inhibitors chemical synthesis, Acetaldehyde Dehydrogenase Inhibitors metabolism, Aldehyde Dehydrogenase 1 Family chemistry, Aldehyde Dehydrogenase 1 Family metabolism, Aldehyde Dehydrogenase, Mitochondrial antagonists & inhibitors, Aldehyde Dehydrogenase, Mitochondrial chemistry, Aldehyde Dehydrogenase, Mitochondrial metabolism, Disulfiram analogs & derivatives, Disulfiram chemical synthesis, Humans, Molecular Docking Simulation, Recombinant Proteins metabolism, Retinal Dehydrogenase chemistry, Retinal Dehydrogenase metabolism, Acetaldehyde Dehydrogenase Inhibitors chemistry, Acetaldehyde Dehydrogenase Inhibitors pharmacology, Aldehyde Dehydrogenase 1 Family antagonists & inhibitors, Disulfiram chemistry, Disulfiram pharmacology, Retinal Dehydrogenase antagonists & inhibitors
- 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.
- Published
- 2022
- Full Text
- View/download PDF