Strong Influence of Ancillary Ligands Containing Benzothiazole or Benzimidazole Rings on Cytotoxicity and Photoactivation of Ru(II) Arene Complexes.

A new family of neutral ruthenium(II) arene complexes of the type [Ru(η6-arene)X(κ2- O, N-L)] (η6-arene = p-cym, bz; X = Cl-, SCN-; HL1 = 2-(2'-hydroxyphenyl)benzimidazole, HL2 = 2-(2'-hydroxyphenyl)benzothiazole) has been synthesized and characterized. The cytotoxic activity of the Ru(II) complexes was evaluated in several tumor cell lines (A549, HepG2 and SW480) both in the dark and after soft irradiation with UV and blue light. None of the complexes bearing benzimidazole (HL1) as a ligand displayed phototoxicity, whereas the complexes with a benzothiazole ligand (HL2) exhibited photoactivation; the sensitivity observed for UV was higher than for blue light irradiation. The interesting results displayed by HL2 and [Ru(η6- p-cym)(NCS)(κ2- O, N-L2)], [3a], in terms of photo cytotoxicity prompted us to analyze their interaction with DNA, both in the dark and under irradiation conditions, in an effort to shed some light on their mechanism of action. The results of this study revealed that HL2 interacts with DNA by groove binding, whereas [3a] interacts by a dual mode of binding, an external groove binding, and covalent binding of the metal center to the guanine moiety. Interestingly, both HL2 and [3a] display a clear preference for AT base pairs, and this causes fluorescence enhancement. Additionally, cleavage of the pUC18 plasmid DNA by the complex is observed upon irradiation. The study of the irradiated form demonstrates that the arene ligand is released to yield species such as [Ru(κ2- O, N-L2)(κ1- S-DMSO)2(µ-SCN)]2 [3c] and [Ru(κ2- O, N-L2)(κ1- S-DMSO)3(SCN)] [3d]. Such photo dissociation occurs even in the absence of oxygen and leads to cytotoxicity enhancement, an effect attributed to the presence of [3d], thus revealing the potential of [3a] as a pro-drug for photoactivated anticancer chemotherapy (PACT).

Binding of Al(iii) to synthetic RNA and metal-mediated strand aggregation.

Over the last few years, focused interest in aluminum has been heightened by recent studies regarding its health effects. Its possible relation with chronic diseases makes it convenient to address more in depth the reactivity of aluminum with biologically relevant molecules. The present work investigates the interaction of the aluminum ion with two synthetic RNAs, poly(rA) and poly(rU), through a detailed thermodynamic and kinetic study. The trivalent aluminum ion was kept in solution by complexation with the cacodylate anion, even at neutral pH, thus making the study with biological molecules feasible. The results obtained by spectrophotometry, circular dichroism, viscometry and thermal stability measurements indicate that aluminium strongly interacts with single and duplex RNA structures. The kinetic experiments point out that, even though cacodylate is required to keep the metal in solution, it actually inhibits the reaction of aluminum with RNA as it converts the metal into an unreactive dimer species. Notably, further interaction occurred in an excess of the aluminum/cacodylate complex, inducing aggregation of single-stranded RNAs. An analysis of the kinetic data has shown that the modes of aggregation of the two RNAs differ and such a difference can be ascribed to the diverse polynucleotide secondary structures. The observed stabilization of multiple-stranded systems by aluminum can serve as a model for future studies due to the interest aroused by this metal in the study of non-canonical nucleic acid structures.

Stabilization of Al(III) solutions by complexation with cacodylic acid: speciation and binding features.

Aluminium ions are believed to play a role in a number of neurological and skeletal disorders in the human body. The study of the biological processes and molecular mechanisms that underlie these pathological disorders is rendered a difficult task due to the wide variety of complex species that result from the hydrolysis of Al(3+) ions. In addition, this ion displays a pronounced tendency to precipitate as a hydroxide, so certain complexing agents should be envisaged to stabilize Al(III) solutions in near physiological conditions. In this work, we show that the common buffer cacodylic acid (dimethylarsinic acid, HCac) interacts with Al(III) to give stable complexes, even at pH 7. After preliminary analyses of the speciation of the metal ion and also of the ligand, a systematic study of the formation of different Al/Cac complexes at different pH values has been conducted. UV-Vis titrations, mass spectrometry NMR measurements and DTF calculations were performed to enlighten the details of the speciation and stoichiometry of Al/Cac complexes. The results altogether show that Al/Cac dimer complexes prevail, but monomer and trimer forms are also present. Interestingly, it was found that cacodylate promotes the formation of such relatively simple complexes, even under conditions where the polymeric form, Al13O4(OH)24(7+), should predominate. The results obtained can help to shed some light into the reactivity of aluminium ions in biological environments.