Probing Platinum-Adenine-N3 Adduct Formation with DNA Minor-Groove Binding Agents

被引：9

作者：

Rao, Lu ^{[1
]}

West, Tiffany K. ^{[2
]}

Saluta, Gilda ^{[2
]}

Kucera, Gregory L. ^{[2
]}

Bierbach, Ulrich ^{[1
]}

机构：

[1] Wake Forest Univ, Dept Chem, Winston Salem, NC 27109 USA

[2] Wake Forest Univ Hlth Sci, Dept Canc Biol, Winston Salem, NC 27157 USA

来源：

CHEMICAL RESEARCH IN TOXICOLOGY | 2010年 / 23卷 / 07期

基金：

美国国家卫生研究院;

关键词：

NONLEAVING GROUP; DAMAGE PROFILE; GENOMIC DNA; PLATINUM; RECOGNITION; TARGET; NUCLEOBASE; ADENINE-N3; SEQUENCE;

D O I：

10.1021/tx100170p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Me-lex(py/py), an adenine-N3-selective alkylating agent, and the reversible minor-groove binder netropsin were used to probe the formation of unusual minor-groove adducts by the cytotoxic hybrid agent PT-ACRAMTU ([IPtCl(en)(ACRAMTU)](NO3)(2); en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyII-1,3-dimethylthiourea). PT-ACRAMTU was found by chemical footprinting to inhibit specific Me-lex-mediated DNA cleavage at several adenine sites but not at nonspecific guanine, which is consistent with the platination of adenine-N3. In a cell proliferation assay, a significant decrease in cytotoxicity was observed for PT-ACRAMTU, when cancer cells were pretreated with netropsin, suggesting that minor-groove adducts in cellular DNA contribute to the biological activity of the hybrid agent.

引用

页码：1148 / 1150

页数：3

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