Enediyne Chimeras for Targeted NAMPT Degradation: Enhancing Cytotoxicity via a Radical Clock.

Authors

Xiang Li, Song Wang, Wei Zhang, Yun Ding, Jiaming Lan, Aiguo Hu

Published in

The Journal of organic chemistry. Jul 27, 2026. Epub Jul 27, 2026.

Abstract

Based on a novel targeted protein degradation platform, Protein-Radical-Oxidation Targeting Enediyne Chimera (PROTEC), a series of chimeric enediyne compounds targeting the oncogenic protein nicotinamide phosphoribosyltransferase (NAMPT) were designed and synthesized. These compounds feature different linker lengths and cyclopropane modifications at the alkyne terminus. Computational studies showed that incorporating the cyclopropane group at the propargyl position facilitates the "radical clock" mechanism, achieving greater spatial separation and weaker orbital interactions between the two radical centers, thereby enhancing hydrogen abstraction ability. The PROTEC-4 compound exhibiting the strongest interaction with NAMPT, as demonstrated by docking studies, established significant cytotoxicity against human ovarian cancer A2780 cells with a half-inhibitory concentration (IC50) of 0.24 μM, indicating great potential for future antitumor drug development.

PMID:
42504523
Bibliographic data and abstract were imported from PubMed on 27 Jul 2026.

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