Pseudopeptides with aldehyde or vinylsulfone warheads: Synthesis and antiproteasomal activity
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
34371374
DOI
10.1016/j.bioorg.2021.105228
PII: S0045-2068(21)00605-2
Knihovny.cz E-resources
- Keywords
- Apoptosis, Inhibitor, Proteasome, Salicylamide, Ubiquitin,
- MeSH
- Aldehydes chemistry pharmacology MeSH
- Proteasome Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Peptides chemistry pharmacology MeSH
- Proteasome Endopeptidase Complex metabolism MeSH
- Sulfones chemistry pharmacology MeSH
- Vinyl Compounds chemistry pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Aldehydes MeSH
- Proteasome Inhibitors MeSH
- Peptides MeSH
- Proteasome Endopeptidase Complex MeSH
- Sulfones MeSH
- Vinyl Compounds MeSH
The comparative study of new proteasome inhibitors based on salicylic acid-modified pseudo-tripeptides terminated with aldehyde or vinylsulfone is presented. We described the synthesis of 11 pairs of pseudopeptides and their properties related to the proteasome inhibition were determined. The effects of integrated amino acids (combinations of leucine, phenylalanine, tryptophan, proline, cyclohexylalanine or norleucine residues) on the activity of the proteasome were investigated. Compounds preferentially inhibited the chymotrypsin β5-subunit of the proteasome in cell-based assays compared with the β1- and β2-subunits, with IC50 values in mid-nanomolar ranges being obtained for the most active members. Our comparative study demonstrated that aldehydes were able to inhibit the proteasome in cells more effectively than vinylsulfones. These results were corroborated by the accumulation of polyubiquitinated proteins in treated cells, GFP accumulation in a reporter cell line and the ability of new compounds to induce apoptotic cell death.
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