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

Abstract

A new family of neutral ruthenium(II) arene complexes of the type [Ru(η 6 -arene)X(κ 2 -O,N-L)] (η 6 -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(η 6 -p-cym)(NCS)(κ 2 -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(κ 2 -O,N-L2)(κ 1 -S-DMSO) 2 (μ-SCN)] 2 [3c] and [Ru(κ 2 -O,N-L2)(κ 1 -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).

Analysis of Ion Pairing in Solid State and Solution in p-Cymene Ruthenium Complexes

“…The neutral chloride complexes I and II of general formula [( p -cym)­Ru­(Cl)­(κ 2 - O^N–L)] ( p -cym = p -cymene; L = L1, L2) previously prepared by us were found to be useful precursors for the synthesis of the new cationic complexes depicted in Scheme . Thus, chloride replacement by the imidazole derivatives MeIm ( N -methylimidazole) and EpipIm (N-ethylpiperidylimidazole) in the presence of a sodium salt (NaCl, NaBF 4 or NaBPh 4 ) yielded [( p -cym)­Ru­(κ 2 -O^N–L)­(MeIm)] + (L = L1 ([ 1 ] + ), L2 ([ 2 ] + )), and [( p -cym)­Ru­(κ 2 -O^N–L1)­(EpipIm)] + ([ 6 ] + ), which were isolated as the corresponding Cl – , BF 4 – , and BPh 4 – salts.…”

“…The coordination bond distances lie in the expected range (close to 2 Å). , The Ru–O (2.066–2.081 Å) and Ru–N bond distances (2.068–2.111 Å) of the chelate ligands are very similar in the different complexes with a longer distance for the Ru–N­(benzothiazolyl) bond (complex [ 3 ]­BF 4 ), as has been previously observed in II (see Scheme ). The Ru–N­(RIm) distance (2.100–2.106 Å) is similar to those in related complexes reported in the literature. , The Ru–C­(average) and Ru–C­(centroid) distances are very similar in the four complexes and are also standard. , The bite angle N1–Ru–O1 is slightly higher for the complex with O^N–L2 (84.02(7) °) than for complexes with the O^N–L1 ligand (82.1–82.9°).…”

“…In general terms, the cationic nature of the complexes agrees with the shift to low-field of almost all the proton resonances of the O^N–L1, O^N–L2, and p -cymene ligands relative to the neutral precursors I – III (see Tables S7–S11 for a better comparison). In addition, the lack of symmetry of the complexes results in the display of two and four signals for the methyl groups of i Pr and the four aromatic protons, respectively, of the p -cymene ligand in the 1 H NMR spectra.…”

The Development of Ru(II)-Based Photoactivated Chemotherapy Agents

“…García et al investigated a neutral Ru(II) arene complex 73 bearing a benzothiazole ligand (HL2) as the bidentate ligand [ 132 ]. The results of this study indicated that the arene ligand is released after irradiation with UV light even in the absence of oxygen and leads to cytotoxicity enhancement, thus revealing the potential of 73 as a prodrug for PACT.…”

Mechanistic study on substitution reaction of a citrato(p-cymene)Ru(ii) complex with sulfur-containing amino acids

“…Especially their anticancer activities have received a great deal of attention. [1][2][3][4][5][6][7][8][9] On the other hand, arene ruthenium(II) complexes have been also applied to synthetic studies as a sort of building block for constructing a series of supramolecules. 10,11 From the pharmacokinetic point of view, thorough studies on the reaction mechanism with bio-related substances in aqueous solution are essential to grasp the chemical species and their transformations in vivo.…”