1. Engineering hypoxia-responsive 6-aminonicotinamide prodrugs for on-demand NADPH depletion and redox manipulation.
- Author
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Li M, Dong Y, Wang Z, Zhao Y, Dai Y, and Zhang B
- Subjects
- Humans, Cell Proliferation drug effects, Molecular Structure, Glucosephosphate Dehydrogenase metabolism, Glucosephosphate Dehydrogenase antagonists & inhibitors, Cell Hypoxia drug effects, Drug Screening Assays, Antitumor, Prodrugs chemistry, Prodrugs pharmacology, Prodrugs chemical synthesis, Oxidation-Reduction, 6-Aminonicotinamide pharmacology, 6-Aminonicotinamide chemistry, NADP metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis
- Abstract
Glucose-6-phosphate dehydrogenase (G6PD) is a promising target in cancer therapy. However, poor cellular uptake and off-target toxicity have impeded the clinical translation of a canonical G6PD inhibitor (6-aminonicotinamide/6AN). Here, we report a prodrug strategy to address this issue. The tailored 6AN prodrug contains an azo-bearing protection moiety. The hydrophobic prodrug showed increased cellular uptake than 6AN and was vulnerable to hypoxia, resulting in NAD(P)H quinone dehydrogenase 1 (NQO1)-triggered cleavage of azo bonds. Intriguingly, the prodrug showed configuration-dependent anti-cancer potency. Despite the lower thermodynamic stability, the cis isomer showed enhanced cellular uptake compared to the trans counterpart due to the increased aqueous solubility. Moreover, the boosted potency of the cis isomer compared to the trans isomer arose from the enhancement of NOQ1-catalyzed 6AN release under hypoxia, a hallmark of solid tumors. The discovery of hypoxia-responsive 6AN prodrugs in the current work opens up new avenues for G6PD-targeting cancer medicines.
- Published
- 2024
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