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.

RuIII Complexes for Anticancer Therapy: The Importance of Being Nucleolipidic

“…In particular, both rapidly replace chlorido and DMSO ligands with water molecules or hydroxide ions. [91][92][93] [94] 620 ± 30 ---AziRu [89] 305 ± 16 441 ± 20 318 ± 12 382 ± 19 Thus, AziRu is not cytotoxic per se -similarly to NAMI-A -against human cancer cells; however, its IC 50 value is half that of NAMI-A towards MCF-7 breast cancer cells (Table 1).…”

Recent Advances in the Development of Indazole‐based Anticancer Agents

“…Apart from the well‐studied indazole‐ruthenium(III) complexes, Cabrera et al. quite recently presented six new imidoyl‐indazole platinum(II) complexes as potential anticancer agents .…”

“…[91] On one hand, indazole can maintain the square-planar geometry of the complexes, which is necessary for forming the DNA lesions. On the other hand, the anticancer effect could be enhanced Apart from the well-studied indazole-ruthenium(III) complexes, [92][93][94] Cabrera et al quite recently presented six new imidoyl-indazole platinum(II) complexesa sp otentiala nticancer agents. [95] In their study,b oth ammonia ligands in cisplatin were substituted by an N,N-imidoyl-indazole system, which served as ab identate ligand, in whicho ne of the N-donors in this ligand belonged to the indazole moiety and the other Ndonor arises from aS chiff base.…”

Development of the application of speciation in chemistry

“…Modifications of this axial ligand affect numerous properties, such as solubility, lipophilicity, and the ligand exchange rate, as well as the ability to bind to HSA and the redox potential of the complex, where all these factors ultimately influence the bioactivity [240,241].…”