title: CF3 Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity.
abstract: 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 (19)F 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 D7.4). The solution behavior of the CF3-functionalized complexes was characterized in phosphate-buffered saline (PBS) using (19)F 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. (19)F 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.
authors.affiliation: Department of Chemistry, Simon Fraser University , 8888 University Drive, Burnaby, BC Canada , V5A 1S6.
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Chang
authors.affiliation: Department of Chemistry, Simon Fraser University , 8888 University Drive, Burnaby, BC Canada , V5A 1S6.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Lewis
authors.affiliation: Department of Chemistry, Simon Fraser University , 8888 University Drive, Burnaby, BC Canada , V5A 1S6.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Prosser
authors.affiliation: Department of Chemistry, Simon Fraser University , 8888 University Drive, Burnaby, BC Canada , V5A 1S6.
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.affiliation: Department of Chemistry, Simon Fraser University , 8888 University Drive, Burnaby, BC Canada , V5A 1S6.
authors.forename: Margarita
authors.initials: M
authors.lastname: Gladkikh
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency , Vancouver, BC Canada , V5Z 4E6.
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
authors.affiliation: Department of Chemistry, Simon Fraser University , 8888 University Drive, Burnaby, BC Canada , V5A 1S6.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Warren
authors.affiliation: Department of Chemistry, Simon Fraser University , 8888 University Drive, Burnaby, BC Canada , V5A 1S6.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Walsby
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055664:Electrochemical Techniques; D004578:Electron Spin Resonance Spectroscopy; D005462:Fluorine Radioisotopes; D019073:HT29 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*; D017975:Ruthenium Compounds; D012709:Serum Albumin / Q000737:chemistry*; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005462:Fluorine Radioisotopes; D007093:Imidazoles; D007191:Indazoles; D009942:Organometallic Compounds; D011725:Pyridines; D017975:Ruthenium Compounds; D012709:Serum Albumin; C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); C000600110:NKP-1339; D012428:Ruthenium