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.
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.
Singh
Sheo B
SB
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. sheo_singh@merck.com
Zink
Deborah L
DL
Liesch
Jerrold M
JM
Mosley
Ralph T
RT
Dombrowski
Anne W
AW
Bills
Gerald F
GF
Darkin-Rattray
Sandra J
SJ
Schmatz
Dennis M
DM
Goetz
Michael A
MA
D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004852:Epoxy Compounds / Q000737:chemistry*; D056572:Histone Deacetylase Inhibitors; D013058:Mass Spectrometry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D013237:Stereoisomerism
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin