Homolysis of Alkoxyamines Triggered by Carbohydrate-Active Enzyme: A Step toward a General Platform to Generate Toxic Alkyl Radicals

Abstract

The rise of drug-resistant pathogens and the dose-limiting side effects of current therapies highlight the urgent need for innovative treatment strategies. We recently demonstrated that hybrid alkoxyamine–peptide conjugates, upon enzymatic cleavage by specific peptidases, undergo C–O bond homolysis to generate highly reactive radical species capable of inducing broad-spectrum damage to pathogenic organisms (cancerous cells, parasites, fungi, etc.). Relying on this concept, we now report on the design and synthesis of a new class of enzyme-triggered, releasing radical prodrugs with a carbohydrate structure as a leaving group. These molecules offer a versatile strategy for the development of next-generation therapeutics that couple enzymatic specificity using glucosidase with controlled radical release to fight resistant and difficult-to-treat infections.