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Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors
Ziad Omran1,2
1Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia.
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.
Insights
New disulfiram-based compounds selectively inhibit aldehyde dehydrogenase-1a1 (ALDH1a1), an enzyme targeted for cancer and inflammation, while avoiding ALDH2 inhibition crucial for alcohol metabolism.
Area of Science:
- Biochemistry
- Medicinal Chemistry
Background:
- Aldehyde dehydrogenase-1a1 (ALDH1a1) is a key enzyme in retinoic acid synthesis, implicated in cancer, obesity, and inflammation.
- Disulfiram inhibits ALDH1a1 and ALDH2 but lacks selectivity.
- ALDH1a1 possesses a larger substrate tunnel than ALDH2, suggesting potential for selective inhibition.
Purpose of the Study:
- To synthesize novel disulfiram analogs with enhanced selectivity for ALDH1a1 over ALDH2.
- To explore the structure-activity relationship of modified disulfiram compounds.
Main Methods:
- Chemical synthesis of novel disulfiram derivatives incorporating (hetero)aromatic rings.
- In vitro enzymatic assays to assess inhibitory activity against ALDH1a1 and ALDH2.
Main Results:
- Several newly synthesized compounds retained the ALDH1a1 inhibitory activity of disulfiram.
- The developed compounds demonstrated complete lack of inhibitory activity against ALDH2.
- Introduction of (hetero)aromatic moieties led to selective ALDH1a1 inhibition.
Conclusions:
- Novel disulfiram analogs offer a promising strategy for selective ALDH1a1 inhibition.
- These selective inhibitors could be therapeutically beneficial for ALDH1a1-related disorders without affecting alcohol metabolism.
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