JiangSu Simcere Pharmaceutical R&D Co., Ltd, and Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18 Xuan Wu Avenue, Nanjing 210042, China.
Bioorg Med Chem Lett. 2011 Aug 15;21(16):4924-7. doi: 10.1016/j.bmcl.2011.06.001. Epub 2011 Jun 16.
A series of benzamide derivatives including two scaffolds were designed and synthesized as potential histone deacetylase inhibitors. Most of synthesized compounds showed moderate enzymatic potency at the same order of magnitude, and compound 12b possessed better potency to the positive control (3.8 μM vs 13.0 μM). It also showed a 50-fold increase in vitro anticancer activity against DU-145 cell-lines. Molecular docking studies were carried out and used to explain the structure-activity relationships observed in vitro. Then we found that the cavity surrounded by ASP104, HIS33, PRO34 and PHE155 may be crucial for the inhibitors' activity. The docking results provide some useful information for future design of more potent inhibitors.
设计并合成了一系列包括两种支架的苯甲酰胺衍生物，作为潜在的组蛋白去乙酰化酶抑制剂。大多数合成的化合物在同一数量级上表现出中等的酶活性，化合物 12b 对阳性对照（3.8 μM 对 13.0 μM）具有更好的活性。它还显示出对 DU-145 细胞系体外抗癌活性增加了 50 倍。进行了分子对接研究，并用于解释体外观察到的构效关系。然后我们发现，由 ASP104、HIS33、PRO34 和 PHE155 包围的腔可能对抑制剂的活性至关重要。对接结果为未来设计更有效的抑制剂提供了一些有用的信息。
