Total Synthesis of Largazole and Its Biological Evaluation
Total Synthesis of Largazole and Its Biological Evaluation
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DOI：
10.1055/s-2008-1078263
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发表时间：
2008-10-01
期刊：
影响因子：
2
通讯作者：
Doi, Takayuk
中科院分区：
文献类型：
--
作者：
Numajiri, Yoshitaka;Takahashi, Takashi;Doi, Takayuk
我们实现了largazole的全合成。以改性的长尾n -乙酰噻唑烷硫酮为原料制备了具有光学活性的对羟基羰基单元。以含cys -2- mecys的三肽为原料，采用步进法和串联环化法制备了4-甲基噻唑-噻唑氨基酯。活化的对羟基羰基单元和4-甲基噻唑-含噻唑的氨基酯酰胺化，然后与N-Fmoc valine酯化，选择性去除c端甲酯和n端Fmoc基团，形成环化前体。大内酰胺化、巯基脱保护和s -酰化提供了大唑。对其s修饰衍生物和合成的大唑进行生物学评价，发现其对组蛋白去乙酰化酶（HDAC）具有较强的抑制活性。
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).