title: Conjugation of Uridine with Oleanolic Acid Derivatives as Potential Antitumor Agents.
abstract: According to fused two bioactive moieties together by bonds covalently and available as a new single hybrid entity known as pharmacophore hybridization, a total of 10 targeted uridine-oleanolic acid hybrids were synthesized. Most of these hybrids showed excellent proliferation inhibition against tested Hep-G2, A549, BGC-823, MCF-7, and PC-3 tumor cell lines (IC50 < 8 μm), even with some IC50 values under 0.1 μm. The detection of cytotoxicity selectivity revealed that hybrids 5 and 18 exhibited low cytotoxicity toward normal human liver cell HL-7702. Further studies revealed that selected hybrid 5 could induce apoptosis in Hep-G2 cells through the investigation of acridine orange/ethidium bromide, Hoechst 33258 fluorescence stainings, and annexin V/propidium iodide assay. It was also found that hybrid 5 could induce mitochondrial membrane potential disruption, arrest Hep-G2 cell line at G1 phase, and activate effector caspase-3/9 to trigger cell apoptosis.
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, 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, China.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Su
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, China.
authors.forename: Jia-Yan
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China.
authors.forename: Yuan-Ting
authors.initials: YT
authors.lastname: Zheng
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, China.
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009828:Oleanolic Acid; D053148:Caspase 3; D014529:Uridine
keywords: apoptosis; cytotoxicity; oleanolic acid; uridine