title: Design and synthesis of celastrol derivatives as anticancer agents.
abstract: 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.
authors: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
authors: Wen-Jian
authors: WJ
authors: Tang
authors: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
authors: Jing
authors: J
authors: Wang
authors: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
authors: Xu
authors: X
authors: Tong
authors: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
authors: Jing-Bo
authors: JB
authors: Shi
authors: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: xhliuhx@163.com.
authors: Xin-Hua
authors: XH
authors: Liu
authors: School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China. Electronic address: ahmupharm@126.com.
authors: Jun
authors: J
authors: Li
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053978:Pentacyclic Triterpenes; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors; D014315:Triterpenes / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C509186:TERT protein, human; D019098:Telomerase; C050414:celastrol
keywords: Anticancer activity; Celastrol derivatives; Cell apoptosis; Telomerase