Design and synthesis of celastrol derivatives as anticancer agents.
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.
['Tang|Wen-Jian|WJ|', 'Wang|Jing|J|', 'Tong|Xu|X|', 'Shi|Jing-Bo|JB|', 'Liu|Xin-Hua|XH|', 'Li|Jun|J|']
D000970:Antineoplastic Agents D017209:Apoptosis D049109:Cell Proliferation D015195:Drug Design D004354:Drug Screening Assays, Antitumor D006801:Humans D008958:Models, Molecular D015394:Molecular Structure D009369:Neoplasms D053978:Pentacyclic Triterpenes D013329:Structure-Activity Relationship D019098:Telomerase D014315:Triterpenes D014407:Tumor Cells, Cultured
Celastrol derivatives Telomerase Anticancer activity Cell apoptosis