title: Water-Soluble Ruthenium(II) Complexes with Chiral 4-(2,3-Dihydroxypropyl)-formamide Oxoaporphine (FOA): In Vitro and in Vivo Anticancer Activity by Stabilization of G-Quadruplex DNA, Inhibition of Telomerase Activity, and Induction of Tumor Cell Apoptosis.
abstract: Three water-soluble ruthenium(II) complexes with chiral 4-(2,3-dihydroxypropyl)-formamide oxoaporphine (FOA) were synthesized and characterized. It was found that these ruthenium(II) complexes exhibited considerable in vitro anticancer activities and that they were the effective stabilizers of telomeric and G-quadruplex-DNA (G4-DNA) in promoter of c-myc, which acted as a telomerase inhibitor targeting G4-DNA and induced cell senescence and apoptosis. Interestingly, the in vitro anticancer activity of 6 (LC-003) was higher than those of 4 (LC-001) and 5 (LC-002), more selective for BEL-7404 cells than for normal HL-7702 cells, and preferred to activate caspases-3/9. The different biological behaviors of the ruthenium complexes could be correlated with the chiral nature of 4-(2,3-dihydroxypropyl)-formamide oxoaporphine. More significantly, 6 exhibited effective inhibitory on tumor growth in BEL-7402 xenograft mouse model and higher in vivo safety than cisplatin. These mechanistic insights indicate that 6 displays low toxicity and can be a novel anticancer drug candidate.
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China.
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Chen
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China.
authors.forename: Qi-Pin
authors.initials: QP
authors.lastname: Qin
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China.
authors.forename: Jiao-Lan
authors.initials: JL
authors.lastname: Qin
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China.
authors.forename: Yu-Lan
authors.initials: YL
authors.lastname: Li
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China.
authors.forename: Yan-Cheng
authors.initials: YC
authors.lastname: Liu
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry*; D005260:Female; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; C000601391:LC-001; C000601390:LC-002; C000601389:LC-003; D012333:RNA, Messenger; D017975:Ruthenium Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014867:Water; D004247:DNA; C509186:TERT protein, human; D019098:Telomerase