Structure and Chemistry of Apicidins, a Class of Novel Cyclic Tetrapeptides without a Terminal α-Keto Epoxide as Inhibitors of Histone Deacetylase with Potent Antiprotozoal Activities
| Autor: | Michael A. Goetz, Gerald F. Bills, Dennis M. Schmatz, Sheo B. Singh, Sandra J. Darkin-Rattray, Deborah L. Zink, Jerrold M. Liesch, Anne W. Dombrowski, Ralph T. Mosley |
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| Rok vydání: | 2002 |
| Předmět: |
Protein Conformation
medicine.drug_class Stereochemistry Antiprotozoal Agents Epoxide Peptide Peptides Cyclic Mass Spectrometry chemistry.chemical_compound parasitic diseases medicine Enzyme Inhibitors Nuclear Magnetic Resonance Biomolecular chemistry.chemical_classification Tetrapeptide Organic Chemistry Stereoisomerism Cyclic peptide Amino acid Histone Deacetylase Inhibitors chemistry Biochemistry Antiprotozoal Epoxy Compounds Histone deacetylase Apicidin |
| Zdroj: | The Journal of Organic Chemistry. 67:815-825 |
| ISSN: | 1520-6904 0022-3263 |
| DOI: | 10.1021/jo016088w |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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