Stabilization of G-Quadruplex DNA, Inhibition of Telomerase Activity, and Tumor Cell Apoptosis by Organoplatinum(II) Complexes with Oxoisoaporphine

被引：153

作者：

Chen, Zhen-Feng ^{[1
]}

Qin, Qi-Pin ^{[1
]}

Qin, Jiao-Lan ^{[1
]}

Liu, Yan-Cheng ^{[1
]}

Huang, Ke-Bin ^{[1
]}

Li, Yu-Lan ^{[1
]}

Meng, Ting ^{[1
]}

Zhang, Guo-Hai ^{[1
]}

Peng, Yan ^{[1
]}

Luo, Xu-Jian ^{[1
]}

Liang, Hong ^{[1
]}

机构：

[1] Guangxi Normal Univ, Sch Pharm & Chem, State Key Lab Cultivat Base Chem & Mol Engn Med R, Yucai Rd 15, Guilin 541004, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 05期

基金：

中国国家自然科学基金;

关键词：

REVERSE-TRANSCRIPTASE GENE; STRUCTURE-BASED DESIGN; C-MYC PROMOTER; QUINDOLINE DERIVATIVES; PLATINUM(II) COMPLEXES; LUMINESCENT PROBES; BINDING-AFFINITY; SMALL-MOLECULE; HUMAN OVARIAN; IN-VITRO;

D O I：

10.1021/jm5012484

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2159 / 2179

页数：21

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