中国科学院广州生物医药与健康研究院蒋晟研究员和周光飚研究员在组蛋白去乙酰化酶抑制剂研究方面取得了重要进展，成功地构建了天然环肽Largazole与组蛋白去乙酰化I型酶的结合模型，以计算机辅助药物设计的方法成功设计合成了一系列全新的环肽。其中化合物7有效抑制HT-29肿瘤细胞的生长（GI50=50 nM），并且在100 μM时对正常细胞无任何毒性。这一研究发现了一批具有细胞水平抑制肿瘤生长活性的组蛋白去乙酰化酶抑制剂，为抗肿瘤候选药物提供了富有前景的药效团模式和先导化合物。相关成果文章“Total Synthesis and Biological Evaluation of Largazole and Derivatives with Promising Selectivity for Cancers Cells”发表在《有机快报》（Organic Letters）上。
组蛋白去乙酰化酶在基因表达和染色体形成等方面起着重要的调节作用，组蛋白去乙酰化酶抑制剂能够阻滞肿瘤细胞生长、诱导肿瘤细胞分化和凋亡。（来源：中国科学院广州生物医药与健康研究院）
Total Synthesis and Biological Evaluation of Largazole and Derivatives with Promising Selectivity for Cancers Cells
Xin Zeng !, Biaolin Yin §, Zheng Hu !, Chenzhong Liao#, Jinglei Liu!, Shang Li!, Zheng Li, Marc C. Nicklaus#, Guangbiao Zhou*! and Sheng Jiang*!
Org. Lett., 2010, 12 (6), pp 1368–1371
DOI: 10.1021/ol100308a
Publication Date (Web): February 25, 2010
The efficient total synthesis of the natural substance largazole is described. Using this strategy, a small library of largazole analogs was developed. Structureactivity relationship studies suggested that the geometry of the alkene in the side chain is critical. While the largazole’s analogues with trans-alkene are potent for the antiproliferative effect, those with cis-alkene are completely inactive. Most importantly, replacement of valine with tyrosine in largazole increased selectivity toward human cancer cells over human normal cells more than 100-fold.
