Total Synthesis of Largazole and Its Biological Evaluation

被引：43

作者：

Numajiri, Yoshitaka ^{[4
]}

Takahashi, Takashi ^{[4
]}

Takagi, Motoki ^{[3
]}

Shin-ya, Kazuo ^{[2
]}

Doi, Takayuk ^{[1
]}

机构：

[1] Tohoku Univ, Grad Sch Pharmaceut Sci, Aoba Ku, Sendai, Miyagi 9808578, Japan

[2] Natl Inst Adv Ind Sci & Technol, Koto Ku, Tokyo 1350064, Japan

[3] JBIC, BIRC, Koto Ku, Tokyo 1350064, Japan

[4] Tokyo Inst Technol, Dept Appl Chem, Meguro Ku, Tokyo 1528552, Japan

来源：

SYNLETT | 2008年 / 16期

关键词：

HDAC inhibitor; macrolactamization; natural products; peptides; total synthesis;

D O I：

10.1055/s-2008-1078263

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

We achieved a total synthesis of largazole. The optically active P-hydroxycarbonyl unit was prepared from a modified Nagao's N-acetylthiazolidinethione. A 4-methylthiazoline-thiazole amino ester was prepared by both a step-by-step method and tandem cyclization from Cys-2-MeCys-containing tripeptide. Amidation of the activated P-hydroxycarbonyl unit and 4-methylthiazoline-thiazole-containing amino ester, followed by esterification with N-Fmoc valine afforded cyclization precursor after selective removal of the methyl ester at the C-terminus and the Fmoc group at the N-terminus. Macrolactamization, deprotection of thiol, and S-acylation provided largazole. Biological evaluation of its S-modified derivatives as well as the synthetic largazole exhibited strong inhibitory activity against histone deacetylases (HDAC).

引用

页码：2483 / 2486

页数：4

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