Issue 30, 2019

Introduction of the α-ketoamide structure: en route to develop hydrogen peroxide responsive prodrugs

Abstract

Leveraging the elevated levels of hydrogen peroxide (H2O2) in cancer, inflammatory diseases and cardiovascular disorders, H2O2-activated promoieties have been widely used in drugs and biomaterials design. However, the overwhelming majority of the promoieties only share the common structure of a H2O2-responsive arylboronic acid/ester moiety with low diversity. We report here an unprecedented strategy to construct novel H2O2-responsive prodrugs based on an α-ketoamide structure. As a proof of concept, we designed and synthesized a panel of α-ketoamide based nitrogen mustard prodrugs, among which KAM-2 showed potent growth inhibitory activity and high selectivity toward cancer cells. The H2O2-trigged decomposition of KAM-2 was validated, and the DNA damaging and apoptosis promoting activity attributed to the released nitrogen mustard were demonstrated. Our work unveils α-ketoamide as a new scaffold for prodrug design and may quickly inspire future developments.

Graphical abstract: Introduction of the α-ketoamide structure: en route to develop hydrogen peroxide responsive prodrugs

Supplementary files

Article information

Article type
Edge Article
Submitted
21 Feb 2019
Accepted
28 Jun 2019
First published
28 Jun 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2019,10, 7156-7162

Introduction of the α-ketoamide structure: en route to develop hydrogen peroxide responsive prodrugs

T. Meng, J. Han, P. Zhang, J. Hu, J. Fu and J. Yin, Chem. Sci., 2019, 10, 7156 DOI: 10.1039/C9SC00910H

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