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.
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BibTeX
@article{trapp2026homolysis,
title = {{Homolysis of Alkoxyamines Triggered by Carbohydrate-Active Enzyme: A Step toward a General Platform to Generate Toxic Alkyl Radicals}},
author = {Mathilde Trapp and Gérard Audran and Sofiane Bourdillon and Jean-Patrick Joly and Sylvain R A Marque and Philippe Mellet and Sophie Thétiot-Laurent and Nicolas Vanthuyne and Pierre Voisin},
journal = {Journal of Medicinal Chemistry},
year = {2026},
month = sep,
doi = {10.1021/acs.jmedchem.6c01135},
url = {https://hal.science/hal-05743758v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Homolysis of Alkoxyamines Triggered by Carbohydrate-Active Enzyme: A Step toward a General Platform to Generate Toxic Alkyl Radicals
AU - Mathilde Trapp
AU - Gérard Audran
AU - Sofiane Bourdillon
AU - Jean-Patrick Joly
AU - Sylvain R A Marque
AU - Philippe Mellet
AU - Sophie Thétiot-Laurent
AU - Nicolas Vanthuyne
AU - Pierre Voisin
PY - 2026
DA - 2026/09/09
JO - Journal of Medicinal Chemistry
DO - 10.1021/acs.jmedchem.6c01135
UR - https://hal.science/hal-05743758v1
AB - 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.
SN - 0022-2623
SN - 1520-4804
ER -