Synthesis and Biological Evaluation of C7-Demethyl Largazole Analogues
Synthesis and Biological Evaluation of C7-Demethyl Largazole Analogues
复制标题
DOI：
10.1002/cmdc.200900125
复制
发表时间：
2009-08-01
期刊：
影响因子：
3.4
通讯作者：
Nan, Fa-Jun
中科院分区：
文献类型：
--
作者：
Chen, Fei;Gao, An-Hui;Nan, Fa-Jun
拉格唑(1)是从蓝藻中分离得到的一种高官能化大环肽。由Luesch和他的同事组成。[1]它由一个应变的16元大环组成，它包括线性融合的4-甲基噻唑啉和噻唑以及3-羟基-7-硫代-4-烯酸单元的酯。后者的一部分构成了侧链，这被证明是有效的组蛋白脱乙酰基酶(HDAC)抑制所必需的，因此该化合物具有抗增殖活性。[2]最近，抑制HDAC活性被临床证实是一种新的治疗癌症的策略。[3]到目前为止，已经报道了几种结构多样的小分子HDAC抑制剂(HDACi)，包括芳基羟氨酸酯、苯甲酰胺、短链脂肪酸、亲电酮和大环肽。[4-7]所有这些HDACi都具有三种药理作用结构，包括锌结合结构域、连接结构域和表面识别结构域。[3]在这些HDACi中，大环肽具有良好的HDAC抑制活性和选择性，因为它们的识别结构域最复杂。一种有希望的大环肽化合物(FK228)是II期临床研究的一部分。自发现以来，16元大环去脂肽精胺(1)因其与FK228高度相似的结构以及同样高的HDAC抑制活性和选择性而受到越来越多的关注。最近报道了几个精唑(1)的全合成和构效关系(SAR)研究。[2，8-12]在本研究中，我们使用LibDock[13]程序和一个组蛋白脱乙酰酶样蛋白(HDLP)[14]的晶体结构来指导我们对精唑(1)的结构优化方法。为了简化16元大环，我们去掉了C7-甲基，得到了2，4‘-联噻唑类似物2(图1)。除了类似物2，C17-同分异构体Ana-
Largazole (1) is a densely functionalized macrocyclic depsipeptide that was isolated from the cyanobacterium Symploca sp. by Luesch and co-workers.[1] It consists of a strained 16-membered macrocycle that incorporates a 4-methylthiazoline linearly fused to a thiazole and an ester of a 3-hydroxy-7-mercaptohept-4-enoic acid unit. Part of the latter moiety constitutes the side chain, which was shown to be essential for the potent histone deacetylase (HDAC) inhibitory, and consequently antiproliferative activity of this compound. Largazole also exhibits high HDAC1 selectivity.[2]Recently, inhibition of HDAC activity was clinically validated as a novel therapeutic strategy for cancer treatment.[3] To date, several structurally diverse small-molecule HDAC inhibitors (HDACi) have been reported, which include aryl hydroxamates, benzamides, short-chain fatty acids, electrophilic ketones, and macrocyclic peptides.[4–7] All of these HDACi share a threemotif pharmacophoric structure that comprises a zinc-binding domain, a linker domain, and a surface recognition domain.[3] Among these HDACi, the macrocyclic peptides possess excellent HDAC inhibition activity and selectivity because their recognition domain moieties are the most complex. One promising macrocyclic peptide compound (FK228) is part of a phase II clinical study. Since its discovery, the 16-membered macrocyclic depsipeptide largazole (1) has received increasing attention because of its high structural similarity to FK228 and its similarly high HDAC inhibitory activity and selectivity. Several total syntheses and structure–activity relationship (SAR) studies of largazole (1) have been reported recently.[2, 8–12] In the present study, we used the LibDock [13] program and the crystal structure of a histone deacetylase-like protein (HDLP)[14] to guide our structural optimization approach to largazole (1). To simplify the 16-membered macrocycle, we eliminated the C7-methyl group to give the 2, 4’-bithiazole analogue 2 (Figure 1). In addition to analogue 2, the C17-epimer ana-