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Structure and chemistry of apicidins, a class of novel cyclic tetrapeptides without a terminal alpha-keto epoxide as inhibitors of histone deacetylase with potent antiprotozoal activities.
- Source :
-
The Journal of organic chemistry [J Org Chem] 2002 Feb 08; Vol. 67 (3), pp. 815-25. - Publication Year :
- 2002
-
Abstract
- Apicidins are a class of cyclic tetrapeptides that do not contain the classical electrophilic alpha-keto epoxide yet are potent (nM) inhibitors of histone deacetylase and antiprotozoal agents. These compounds showed broad-spectrum activities against the apicomplexan family of protozoa including Plasmodium sp (malarial parasite), Toxoplasma gondii, Cryptosporidium sp., and Eimeria sp. These cyclic peptides contain a beta-turn amino acid (R)-Pip or (R)-Pro, (S)-N-methoxy Trp, (S)-Ile, or (S)-Val, and either (S)-2-amino-8-oxodecanoic acid or a modified (S)-2-amino-8-oxodecanoic acid. The isolation and structure elucidation of new apicidins from two Fusarium species, temperature-dependent NMR studies of apicidin, NMR and molecular modeling based conformation of the 12-membered macrocyclic ring, and selected chemical modifications of apicidin have been detailed in this paper. The cyclic nature of the peptide, the C-8 keto group, and the tryptophan are all critical for the biological activity.
- Subjects :
- Antiprotozoal Agents pharmacology
Enzyme Inhibitors pharmacology
Mass Spectrometry
Nuclear Magnetic Resonance, Biomolecular
Peptides, Cyclic pharmacology
Protein Conformation
Stereoisomerism
Antiprotozoal Agents chemistry
Enzyme Inhibitors chemistry
Epoxy Compounds chemistry
Histone Deacetylase Inhibitors
Peptides, Cyclic chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3263
- Volume :
- 67
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of organic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11856024
- Full Text :
- https://doi.org/10.1021/jo016088w