School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
Eur J Med Chem. 2015 May 5;95:166-73. doi: 10.1016/j.ejmech.2015.03.039. Epub 2015 Mar 18.
A series of celastrol derivatives as potential telomerase inhibitors were designed and synthesized. The bioassays demonstrated that title compounds displayed potent anticancer activities against SGC-7901, SMMC-7721, MGC-803 and HepG-2 cell lines, among them, compounds 3c and 3d which containing hydrophilicity moieties exhibited high anti-proliferative activities (IC50 = 0.10-1.22 μM). The preliminary mechanism of antitumor action indicated that title compound 3c could induce significant SMMC-7721 cells apoptosis. A modified TRAP assay showed that compounds 3c and 3d displayed the most potent inhibitory activity with IC50 values at 0.11 and 0.34 μM, respectively. And there was a good correlation between telomerase inhibition and anti-proliferative inhibition of SMMC-7721 cells. Moreover, molecular docking indicated that the active compound 3c was nicely bound into the telomerase hTERT active site, hydrophobic, van der Waals and two hydrogen bond interactions with conserved residues ASP 628 and TYR 949 were found.
设计并合成了一系列作为潜在端粒酶抑制剂的雷公藤红素衍生物。生物测定表明，标题化合物对 SGC-7901、SMMC-7721、MGC-803 和 HepG-2 细胞系表现出很强的抗癌活性，其中含有亲水性部分的化合物 3c 和 3d 表现出很高的抗增殖活性（IC50=0.10-1.22μM）。抗肿瘤作用的初步机制表明，标题化合物 3c 可诱导 SMMC-7721 细胞发生明显的凋亡。改良的 TRAP 测定表明，化合物 3c 和 3d 的抑制活性最强，IC50 值分别为 0.11 和 0.34μM。而且，端粒酶抑制与 SMMC-7721 细胞增殖抑制之间存在良好的相关性。此外，分子对接表明活性化合物 3c 很好地结合到端粒酶 hTERT 的活性部位，与保守残基 ASP 628 和 TYR 949 存在疏水、范德华和两个氢键相互作用。
