title: Synthesis of oleanolic acid dimers linked at C-28 and evaluation of anti-tumor activity.
abstract: Five dimeric oleanolic acids linked at C-28 by 1,6-hexanediamine, or built around the carbon chains of varying lengths between two carboxyl groups were synthesized, to investigate the effect of internal spacer length and species upon the stereochemical features and anti-tumor activity of the resultant bis-oleanolic acids. The IC50 values of these dimeric compounds for cytotoxicity evaluation in vitro against Hep-G2, A549, BGC-823, MCF-7 and PC-3 tumor cell lines, were mainly under 10.0 μM. This result was much better than the inhibition of proliferation against tested tumor cell lines of the monomer oleanolic acid and the commercial anticancer drug 5-fluorouracil. The cytotoxicity selectivity detection revealed that dimer 11c exhibited low cytotoxicity towards normal human liver cell HL-7702. A combination of fluorescence staining observation and flow cytometric analysis indicated that 11c could induce Hep-G2 cell apoptosis. Molecular mechanism studies suggested that 11c induced apoptosis is mediated through the intrinsic apoptotic pathway with changes in mitochondrial membrane potential by finally activating effector caspase-3/9 to trigger cell apoptosis. Further studies revealed that 11c caused cell cycle arrest at G1 phase in Hep-G2 cells. Taken together, these results suggest that 11c may be a potential candidate for further cancer research.
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Ke-Guang
authors.initials: KG
authors.lastname: Cheng
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Su
authors.affiliation: Department of Obstetrics and Gynecology, Nanjing Jinling Hospital, Nanjing 210002, PR China.
authors.forename: Lin-Dong
authors.initials: LD
authors.lastname: Yang
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tongiia Xiang, Nanjing 210009, PR China. Electronic address: junincpu@yahoo.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin 541004, PR China. Electronic address: chenzfubc@yahoo.com.
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D008968:Molecular Conformation; D009828:Oleanolic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009828:Oleanolic Acid
keywords: Anti-tumor activity; Apoptosis; Cytotoxicity; Dimers; Oleanolic acid