Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: synthesis and biological evaluation.
Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: synthesis and biological evaluation.
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DOI：
10.1021/jm200432a
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发表时间：
2011-11-10
影响因子：
7.3
通讯作者：
Tillekeratne, L. M. Viranga
中科院分区：
文献类型：
--
作者：
Bhansali, Pravin;Hanigan, Christin L.;Casero, Robert A., Jr.;Tillekeratne, L. M. Viranga
组蛋白脱乙酰酶抑制剂 largazole 1 是通过收敛方法合成的，该方法涉及多种高效且高产的单锅多步骤方案。使用叔丁基作为硫醇保护基团的最初尝试被证明是有问题的，并且通过改用三苯甲基保护基团来完成合成。该合成方案为许多新的拉格唑类似物提供了一种便捷的方法。合成了三种与 Zn2+ 螯合的具有多个杂原子的侧链类似物，并评估了它们的生物活性。它们在 HCT116 结肠癌细胞系生长抑制和诱导整体 H3 乙酰化增加方面的效力不如拉格唑 1。 Lagazole 1 和三个侧链类似物对 HDAC6 没有影响，α-微管蛋白乙酰化没有增加，表明这一点。
The histone deacetylase inhibitor, largazole 1 was synthesized by a convergent approach which involved several efficient and high yielding single pot multistep protocols. Initial attempts using t-butyl as thiol protecting group proved problematic and synthesis was accomplished by switching to trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn2+ were synthesized and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6 as indicated by the lack of increased acetylation of α-tubulin.
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影响因子：
5.2
作者：
Bowers AA;West N;Newkirk TL;Troutman-Youngman AE;Schreiber SL;Wiest O;Bradner JE;Williams RM
通讯作者：
Williams RM
影响因子：
2
作者：
Ren, Qi;Dai, Lu;Ye, Tao
通讯作者：
Ye, Tao
影响因子：
15
作者：
OHTANI, I;KUSUMI, T;KAKISAWA, H
通讯作者：
KAKISAWA, H
影响因子：
3.4
作者：
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通讯作者：
Nan, Fa-Jun
影响因子：
15
作者：
Bowers, Albert;West, Nathan;Taunton, Jack;Schreiber, Stuart L.;Bradner, James E.;Williams, Robert M.
通讯作者：
Williams, Robert M.