通过点击化学的组蛋白去乙酰化酶抑制剂
Histone deacetylase inhibitors through click chemistry.
作者信息
Shen Jie, Woodward Robert, Kedenburg James Patrick, Liu Xianwei, Chen Min, Fang Lanyan, Sun Duxin, Wang Peng George
机构信息
Department of Biochemistry, The Ohio State University, 876 Biological Sciences Building, 484 West 12th Avenue, Columbus, Ohio 43210, USA.
出版信息
J Med Chem. 2008 Dec 11;51(23):7417-27. doi: 10.1021/jm8005355.
Histone deacetylase inhibitors (HDACi) are a relatively new class of chemotherapy agents. Herein, we report a click-chemistry based approach to the synthesis of HDACi. Fourteen agents were synthesized from the combination of two alkyne and seven azido precursors. The inhibition of HDAC1 and HDAC8 was then determined by in vitro enzymatic assays, after which the cytotoxicity was evaluated in the NCI human cancer cell line screen. A lead compound 5 g (NSC746457) was discovered that inhibited HDAC1 at an IC(50) value of 104 +/- 30 nM and proved quite potent in the cancer cell line screen with GI(50) values ranging from 3.92 microM to 10 nM. Thus, this click HDACi design has provided a new chemical scaffold that has not only revealed a lead compound, but one which is easily amendable to further structural modifications given the modular nature of this approach.
组蛋白去乙酰化酶抑制剂（HDACi）是一类相对较新的化疗药物。在此，我们报告一种基于点击化学的HDACi合成方法。通过两种炔烃和七种叠氮基前体的组合合成了十四种化合物。然后通过体外酶促试验测定HDAC1和HDAC8的抑制作用，之后在NCI人类癌细胞系筛选中评估细胞毒性。发现了一种先导化合物5g（NSC746457），其对HDAC1的IC（50）值为104±30 nM，并且在癌细胞系筛选中显示出相当强的活性，GI（50）值范围为3.92 microM至10 nM。因此，这种点击HDACi设计提供了一种新的化学支架，不仅揭示了一种先导化合物，而且鉴于该方法的模块化性质，很容易进行进一步的结构修饰。
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