title: Synthesis and biological evaluation of novel spin labeled 18β-glycyrrhetinic acid derivatives.
abstract: Eighteen novel spin-labeled 18β-glycyrrhetinic acid (GA) derivatives were designed, synthesized, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU-145, KB and KBvin). Most of the derivatives showed more significant cytotoxicity than that of the parent compound GA. The best compound, 6j, with a tryptophan amino moiety and piperidine nitroxyl radical showed GI(50) values of 13.7-15.0 μM, and was fivefold more potent than GA. In a mechanism of action study, compound 7a was confirmed as a 20S proteasome inhibitor in both in vitro and cell-based assays. These findings support further optimization efforts based on 18β-GA as a lead compound to develop potential anticancer drug candidates.
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA.
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Liu
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Chih-Ya
authors.initials: CY
authors.lastname: Wang
authors.forename: Chin-Ho
authors.initials: CH
authors.lastname: Chen
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yang
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; C119129:18alpha-glycyrrhetinic acid; D046988:Proteasome Endopeptidase Complex; D006034:Glycyrrhetinic Acid