A series of potent and selective, triazolylphenyl-based histone deacetylases inhibitors with activity against pancreatic cancer cells and Plasmodium falciparum
A series of potent and selective, triazolylphenyl-based histone deacetylases inhibitors with activity against pancreatic cancer cells and Plasmodium falciparum
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DOI：
10.1021/jm701606b
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发表时间：
2008-06-26
影响因子：
7.3
通讯作者：
Kozikowski, Alan P.
中科院分区：
文献类型：
--
作者：
Chen, Yufeng;Lopez-Sanchez, Miriam;Kozikowski, Alan P.
发现抑制各种HDAC亚型的规则可能是确定作为基因转录表观遗传调节剂的改进治疗方法的关键。本文研究了一组基于三唑苯基的HDACIs的CAP区域的修饰结果，并表明苯基环上的取代性质对HDAC1和HDAC6的选择性起作用，达到了低至中等的选择性（2-51倍）。鉴于三唑苯基配体6b在抑制HDAC6中的选择性和效力（IC50 = 1.9 nM），该化合物代表了一个有价值的研究工具和进一步化学修饰的候选物。最后，对这些新hdac进行了抗肿瘤和抗疟疾活性的研究，验证了hdac 10c的优越活性。
The discovery of the rules governing the inhibition of the various HDAC isoforms is likely to be key to identifying improved therapeutics that act as epigenetic modulators of gene transcription. Herein we present results on the modification of the CAP region of a set of triazolylphenyl-based HDACIs, and show that the nature of substitution on the phenyl ring plays a role in their selectivity for HDAC1 versus HDAC6, with low to moderate selectivity (2-51-fold) being achieved. In light of the valuable selectivity and potency that were identified for the triazolylphenyl ligand 6b in the inhibition of HDAC6 (IC50 = 1.9 nM), this compound represents a valuable research tool and a candidate for further chemical modifications. Lastly, these new HDACIs were studied for both their anticancer and antimalarial activity, which serve to validate the superior activity of the HDACI 10c.