Synthesis, Aqueous Reactivity, and Biological Evaluation of Carboxylic Acid Ester-Functionalized Platinum-Acridine Hybrid Anticancer Agents

被引:44
作者
Graham, Leigh A. [1 ]
Suryadi, Jimmy [1 ]
West, Tiffany K. [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, Sect Hematol & Oncol, Dept Internal Med, Winston Salem, NC 27157 USA
基金
美国国家卫生研究院;
关键词
CELL LUNG-CANCER; DNA INTERACTIONS; PALLADIUM(II) COMPLEXES; ANTITUMOR AGENT; CISPLATIN; REPAIR; CHEMOTHERAPY; EXPRESSION; RESISTANCE; DESIGN;
D O I
10.1021/jm300879k
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis of platinum-acridine hybrid agents containing carboxylic acid ester groups is described. The most active derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-231) cell lines than cisplatin. Inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and nonsmall cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Introduction of the ester groups did not affect the cytotoxic properties of the hybrids, which form the same monofunctional-intercalative DNA adducts as the parent compounds, as demonstrated in a plasmid unwinding assay. In-line high-performance liquid chromatography and electrospray mass spectrometry (LC-ESMS) shows that the ester moieties undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form carboxylate chelates. Potential applications of the chloride-sensitive ester hydrolysis as a self-immolative release mechanism for tumor-selective delivery of platinum-acridines are discussed.
引用
收藏
页码:7817 / 7827
页数:11
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