CF3 Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity

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• 作者：Stephanie. W. Chang ; Andrew R. Lewis ; Kathleen E. Prosser ; John R. Thompson ; Margarita Gladkikh ; Marcel B. Bally ; Jeffrey J. Warren ; Charles J. Walsby
• 刊名：Inorganic Chemistry
• 出版年：2016
• 出版时间：May 16, 2016
• 年：2016
• 卷：55
• 期：10
• 页码：4850-4863
• 全文大小：693K
• 年卷期：0
• ISSN：1520-510X

文摘

The Ru(III) complexes indazolium [trans-RuCl₄(1H-indazole)₂] (KP1019) and sodium [trans-RuCl₄(1H-indazole)₂] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics. Trifluoromethyl derivatives of these compounds and their imidazole and pyridine analogues were synthesized to probe the effect of ligand lipophilicity on the pharmacological properties of these types of complexes. Addition of CF₃ groups also provided a spectroscopic handle for ¹⁹F NMR studies of ligand exchange processes and protein interactions. The lipophilicities of the CF₃-functionalized compounds and their unsubstituted parent complexes were quantified by the shake-flask method to give the distribution coefficient D at pH 7.4 (log D_7.4). The solution behavior of the CF₃-functionalized complexes was characterized in phosphate-buffered saline (PBS) using ¹⁹F NMR, electron paramagnetic resonance (EPR), and UV–vis spectroscopies. These techniques, along with fluorescence competition experiments, were also used to characterize interactions with human serum albumin (HSA). From these studies it was determined that increased lipophilicity correlates with reduced solubility in PBS but enhancement of noncoordinate interactions with hydrophobic domains of HSA. These protein interactions improve the solubility of the complexes and inhibit the formation of oligomeric species. EPR measurements also demonstrated the formation of HSA-coordinated species with longer incubation. ¹⁹F NMR spectra show that the trifluoromethyl complexes release axial ligands in PBS and in the presence of HSA. In vitro testing showed that the most lipophilic complexes had the greatest cytotoxic activity. Addition of CF₃ groups enhances the activity of the indazole complex against A549 nonsmall cell lung carcinoma cells. Furthermore, in the case of the pyridine complexes, the parent compound was inactive against the HT-29 human colon carcinoma cell line but showed strong cytotoxicity with CF₃ functionalization. Overall, these studies demonstrate that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these types of Ru(III) complexes.