Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor.
Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor.
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DOI：
10.1021/ja8033763
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发表时间：
2008-08-20
影响因子：
15
通讯作者：
Williams, Robert M.
中科院分区：
文献类型：
--
作者：
Bowers, Albert;West, Nathan;Taunton, Jack;Schreiber, Stuart L.;Bradner, James E.;Williams, Robert M.
本文报道了最近发现的天然物质拉唑（1）及其活性代谢产物拉唑硫醇（2）的高效全合成。合成需要八个线性步骤，并且以37%的总产率进行。研究表明，largazole是一种前药，通过从3-羟基-7-巯基庚-4-烯酸部分去除辛酰基残基活化，生成活性代谢物largazole硫醇（2），这是一种非常有效的I类组蛋白脱乙酰酶抑制剂。已将合成的largazole和largazole硫醇（2）与FK 228和SAHA并行评价对HDAC 1、2、3和6的抑制作用。进一步测定了拉格唑和拉格唑硫醇对一组化学抗性黑素瘤细胞系的细胞毒性活性，发现拉格唑的细胞毒性显著高于拉格唑硫醇;这种差异分别归因于两种物质的细胞渗透性差异。
The efficient total synthesis of the recently described natural substance largazole (1) and it’s active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug, that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite largazole thiol (2) which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and the largazole thiol (2) have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference being attributed to differences in cell permeability of the two substances, respectively.
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影响因子：
1.8
作者：
Lange, UEW;Schäfer, B;Mack, H
通讯作者：
Mack, H
影响因子：
15
作者：
Taori, Kanchan;Paul, Valerie J.;Luesch, Hendrik
通讯作者：
Luesch, Hendrik
影响因子：
5.2
作者：
Smith, ND;Goodman, M
通讯作者：
Goodman, M
DOI：
10.2174/1568011054866946
发表时间：
2005-09-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Moradei, Oscar;Maroun, Christiane R.;Vaisburg, Arkadii
通讯作者：
Vaisburg, Arkadii
影响因子：
15
作者：
Li, KW;Wu, J;Simon, JA
通讯作者：
Simon, JA