College of Food and Bioengineering, Xihua University, Sichuan 610039, China.
College of Science, Xihua University, Sichuan 610039, China.
Molecules. 2019 Jul 26;24(15):2724. doi: 10.3390/molecules24152724.
Human sirtuin 2 (SIRT2), a member of the sirtuin family, has been considered as a promising drug target in cancer, neurodegenerative diseases, type II diabetes, and bacterial infections. Thus, SIRT2 inhibitors have been involved in effective treatment strategies for related diseases. Using previously established fluorescence-based assays for SIRT2 activity tests, the authors screened their in-house database and identified a compound, 4-(5-((3-(quinolin-5-yl)ureido)methyl)furan-2-yl)benzoic acid (), which displayed 63 ± 5% and 35 ± 3% inhibition against SIRT2 at 100 μM and 10 μM, respectively. The structure-activity relationship (SAR) analyses of a series of synthesized (5-phenylfuran-2-yl)methanamine derivatives led to the identification of a potent compound with an IC value of 2.47 μM, which is more potent than AGK2 (IC = 17.75 μM). Meanwhile, likely possesses better water solubility (cLogP = 1.63 and cLogS = -3.63). Finally, the molecular docking analyses indicated that fitted well with the induced hydrophobic pocket of SIRT2.
人源 sirtuin 2（SIRT2）作为 sirtuin 家族的一员，被认为是癌症、神经退行性疾病、2 型糖尿病和细菌感染等相关疾病的一个很有前途的药物靶点。因此，SIRT2 抑制剂已经被应用于相关疾病的有效治疗策略中。本研究作者利用先前建立的基于荧光的 SIRT2 活性测试方法，从他们的内部数据库中筛选出一种化合物，4-(5-((3-(喹啉-5-基)脲基)甲基)呋喃-2-基)苯甲酸()，其在 100 μM 和 10 μM 时对 SIRT2 的抑制率分别为 63 ± 5%和 35 ± 3%。一系列合成的(5-苯基呋喃-2-基)甲胺衍生物的构效关系（SAR）分析，确定了一种强效化合物，其 IC 值为 2.47 μM，比 AGK2（IC = 17.75 μM）更有效。同时，化合物可能具有更好的水溶性（cLogP = 1.63，cLogS = -3.63）。最后，分子对接分析表明，化合物与 SIRT2 的诱导疏水性口袋契合良好。
