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首页> 外文期刊>Journal of Medicinal Chemistry >Histone Deacetylase Inhibitors through Click Chemistry
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Histone Deacetylase Inhibitors through Click Chemistry

机译：通过点击化学的组蛋白脱乙酰基酶抑制剂

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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 5g (NSC746457) was discovered that inhibited HDAC1 at an IC50 value of 104 +/- 30 nM and proved quite potent in the cancer cell line screen with GI(50) values ranging from 3.92 mu M 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.
机译：组蛋白脱乙酰基酶抑制剂（HDACi）是一类相对较新的化学治疗剂。在此，我们报告了一种基于点击化学的方法来合成HDACi。由两个炔烃和七个叠氮基前体的组合合成了十四种试剂。然后通过体外酶法测定对HDAC1和HDAC8的抑制作用，然后在NCI人癌细胞系筛选中评估其细胞毒性。发现了5g的先导化合物（NSC746457）以104 +/- 30 nM的IC50值抑制HDAC1，并在癌细胞系筛选中证明其非常强大，GI（50）值在3.92μM至10 nM的范围内。因此，这种点击式HDACi设计提供了一种新的化学支架，该支架不仅揭示了一种铅化合物，而且鉴于这种方法的模块化性质，可以轻松地对其进行进一步的结构修饰。

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