Total synthesis and molecular target of largazole, a histone deacetylase inhibitor
Total synthesis and molecular target of largazole, a histone deacetylase inhibitor
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DOI：
10.1021/ja8013727
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发表时间：
2008-07-02
影响因子：
15
通讯作者：
Luesch, Hendrik
中科院分区：
文献类型：
--
作者：
Ying, Yongcheng;Taori, Kanchan;Luesch, Hendrik
的简洁和收敛的合成（8个步骤，19%的总收率），其扩展到一系列的关键类似物的制备，和largazole的分子目标和药效团的全部细节进行了描述。largazole合成的核心是用于形成应变的16元缩肽核心的大环化反应，随后是用于安装硫酯的烯烃交叉复分解反应。对largazole及其关键类似物（包括乙酰基类似物、巯基类似物和羟基类似物）的生物学评价表明，组蛋白脱乙酰酶（HDAC）是largazole的分子靶点，largazole是I类HDAC抑制剂。此外，构效关系（SAR）研究表明，巯基是天然产物的药效团。Largazole的HDAC抑制活性与其抗增殖活性相关。
Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the preparation of a series of key analogues, and the molecular target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biological evaluation of largazole and its key analogues, including an acetyl analogue, a thiol analogue, and a hydroxyl analogue, suggested that histone deacetylases (HDACs) are molecular targets of largazole and largazole is a class I HDAC inhibitor. In addition, structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.