Abstract
The first structure-activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P1, as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CHCH-SO 2Me was the most potent inhibitor of caspase-3 in the series, with a IC50 of 29 μM and a second-order rate constant of inactivation, kinact/Ki, of 1.5 M-1 s-1. Computational studies suggest that the second amino acid occupies position S3 of the enzyme. In addition, Fmoc-Val-Asp-trans-CHCH-SO 2Ph was inactive for caspase-7 for the tested concentrations. The first structure-activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for caspase-3 inhibition.
Original language | English |
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Pages (from-to) | 3858-3863 |
Number of pages | 6 |
Journal | European Journal of Medicinal Chemistry |
Volume | 45 |
Issue number | 9 |
DOIs | |
Publication status | Published - Sept 2010 |
Externally published | Yes |
Keywords
- Caspase-3 inhibitor
- Irreversible inhibitor
- Michael acceptor
- Vinyl sulfone