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

被引：118

作者：

Singh, SB ^{[1
]}

Zink, DL ^{[1
]}

Liesch, JM ^{[1
]}

Mosley, RT ^{[1
]}

Dombrowski, AW ^{[1
]}

Bills, GF ^{[1
]}

Darkin-Rattray, SJ ^{[1
]}

Schmatz, DM ^{[1
]}

Goetz, MA ^{[1
]}

机构：

[1] Merck Res Labs, Rahway, NJ 07065 USA

来源：

JOURNAL OF ORGANIC CHEMISTRY | 2002年 / 67卷 / 03期

关键词：

D O I：

10.1021/jo016088w

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Apicidins are a class of cyclic tetrapeptides that do not contain the classical electrophilic a-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 U-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.

引用

页码：815 / 825

页数：11

共 29 条

[1] Extracting information from the temperature gradients of polypeptide NH chemical shifts .1. The importance of conformational averaging [J].