title: Stabilization of G-quadruplex DNA, inhibition of telomerase activity, and tumor cell apoptosis by organoplatinum(II) complexes with oxoisoaporphine.
abstract: Two G-quadruplex ligands [Pt(L(a))(DMSO)Cl] (Pt1) and [Pt(L(b))(DMSO)Cl] (Pt2) have been synthesized and fully characterized. The two complexes are more selective for SK-OV-3/DDP tumor cells versus normal cells (HL-7702). It was found that both Pt1 and Pt2 could be a telomerase inhibitor targeting G-quadruplex DNA. This is the first report demonstrating that telomeric, c-myc, and bcl-2 G-quadruplexes and caspase-3/9 preferred to bind with Pt2 rather than Pt1, which also can induce senescence and apoptosis. The different biological behavior of Pt1 and Pt2 may correlate with the presence of a 6-hydroxyl group in L(b). Importantly, Pt1 and Pt2 exhibited higher safety in vivo and more effective inhibitory effects on tumor growth in the HCT-8 and NCI-H460 xenograft mouse model, compared with cisplatin. Taken together, these mechanistic insights indicate that both Pt1 and Pt2 display low toxicity and could be novel anticancer drug candidates.
authors: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University , Yucai Road 15, Guilin 541004, P. R. China.
authors: Zhen-Feng
authors: ZF
authors: Chen
authors: Qi-Pin
authors: QP
authors: Qin
authors: Jiao-Lan
authors: JL
authors: Qin
authors: Yan-Cheng
authors: YC
authors: Liu
authors: Ke-Bin
authors: KB
authors: Huang
authors: Yu-Lan
authors: YL
authors: Li
authors: Ting
authors: T
authors: Meng
authors: Guo-Hai
authors: GH
authors: Zhang
authors: Yan
authors: Y
authors: Peng
authors: Xu-Jian
authors: XJ
authors: Luo
authors: Hong
authors: H
authors: Liang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001060:Aporphines / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D016922:Cellular Senescence; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005455:Fluorescent Antibody Technique; D054856:G-Quadruplexes; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D001060:Aporphines; D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D004247:DNA; D019098:Telomerase