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

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• 作者：Leigh A. Graham ; Jimmy Suryadi ; Tiffany K. West ; Gregory L. Kucera ; Ulrich Bierbach
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7817-7827
• 全文大小：496K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

The synthesis of platinum鈥揳cridine 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鈥搃ntercalative 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鈥揳cridines are discussed.