Engineering hypoxia-responsive 6-aminonicotinamide prodrugs for on-demand NADPH depletion and redox manipulation

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Glucose-6-phosphate dehydrogenase (G6PD) is a key metabolic enzyme and a potential therapeutic target in cancer treatment.
• The canonical G6PD inhibitor, 6-aminonicotinamide (6AN), faces challenges in clinical application due to poor cellular uptake and off-target toxicity.

Purpose of the Study:

• To develop a prodrug strategy to enhance the delivery and efficacy of 6AN for cancer therapy.
• To investigate the role of hypoxia and NQO1 in the targeted release and activation of the 6AN prodrug.
• To evaluate the anti-cancer potency of different isomers of the 6AN prodrug.

Main Methods:

• Synthesis of a tailored 6AN prodrug featuring an azo-bearing protection moiety.
• Assessment of cellular uptake and cytotoxicity of the prodrug compared to 6AN.
• Investigation of hypoxia-induced prodrug cleavage mediated by NAD(P)H quinone dehydrogenase 1 (NQO1).
• Comparative analysis of the anti-cancer potency of cis and trans isomers of the prodrug.

Main Results:

• The hydrophobic 6AN prodrug exhibited increased cellular uptake compared to 6AN.
• The prodrug was selectively cleaved under hypoxic conditions, releasing 6AN in an NQO1-dependent manner.
• The cis isomer demonstrated superior anti-cancer potency over the trans isomer, attributed to enhanced cellular uptake and more efficient NQO1-catalyzed 6AN release under hypoxia.
• Hypoxia, a characteristic of solid tumors, significantly enhanced the efficacy of the cis isomer.

Conclusions:

• The developed hypoxia-responsive 6AN prodrug strategy effectively overcomes the limitations of 6AN, improving its therapeutic potential.
• The configuration-dependent activity highlights the importance of isomer-specific drug design.
• This approach offers a promising new avenue for developing targeted G6PD inhibitors for cancer therapy, particularly for solid tumors.