Conformational control of anticancer activity: the application of arene-linked dinuclear ruthenium(ii) organometallics

Benjamin S Murray,Paul J Dyson,Rosario Scopelliti,Laure Menin

doi:10.1039/c4sc00116h

Benjamin S Murray, Paul J Dyson + Show 2 more

Open Access

https://doi.org/10.1039/c4sc00116h

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Abstract

Dinuclear metal complexes have emerged as a promising class of biologically active compounds which possess unique anticancer activity. Here, we describe a novel series of arene-linked dinuclear organometallic Ru(II) complexes, where the relative conformation of the ruthenium centres is controlled by the stereochemical configuration of 1,2-diphenylethylenediamine linker moieties, as confirmed by X-ray crystallography. The reactivity and cytotoxicity of these compounds is compared to flexible dinuclear and mononuclear analogues, demonstrating in all cases the complexes can undergo aquation, coordinate to typical biological donor ligands and importantly, in the case of dinuclear analogues, crosslink oligonucleotide and peptide sequences. Differences in the conformation of the isomeric dinuclear compounds lead to significantly different levels of cytotoxicity against A2780, A2780cisR and HEK-293 cell lines; isomers with a closed conformation are significantly more cytotoxic than isomers with a more open conformation and they are also significantly less susceptible to acquired resistance mechanisms operating in the A2780cisR cell line. These rigid dinuclear compounds possess markedly increased cytotoxicity relative to the non-cytotoxic mononuclear analogues that does not appear to be related to differences in complex lipophilicity or cellular uptake, which, in general, remain similar in magnitude across the series. Thus, the molecular conformation of such dinuclear species may be crucial in determining the nature of the adducts formed on coordination to biological targets in a cellular environment, and opens up a novel route toward the development of more active metal-based anticancer agents.

Highlights

Metal-based compounds offer considerable potential in medicinal chemistry where the careful choice of metal may afford compounds possessing geometrical, coordination and potentially catalytic properties not accessible through purely organic molecules
Differences in the conformation of the isomeric dinuclear compounds lead to significantly different levels of cytotoxicity against A2780, A2780cisR and HEK-293 cell lines; isomers with a closed conformation are significantly more cytotoxic than isomers with a more open conformation and they are significantly less susceptible to acquired resistance mechanisms operating in the A2780cisR cell line
Each oxalato-protected ruthenium complex was successfully converted to its chloridoanalogue by dissolution in an anhydrous solution of HCl in methanol – the yellow solutions immediately turned red in colour followed by precipitation of the desired dinuclear compounds 3b–6b as their HCl salts, or in the case of monomer analogue 2b the product was obtained by precipitation with diethyl ether

Summary

Introduction

Metal-based compounds offer considerable potential in medicinal chemistry where the careful choice of metal may afford compounds possessing geometrical, coordination and potentially catalytic properties not accessible through purely organic molecules. Ruthenium-based organometallic compounds constitute a rapidly developing eld that continues to yield complexes exhibiting diverse biological activity.[2] Prominent examples include the [Ru(h6-arene)(en)Cl]+ family of organometallics that has yielded compounds with a comparable cytotoxicity to that of cisplatin in certain cell lines.[3] Structurally related compounds based on the [Ru(h6-arene)(L)Cl]+ scaffold, with organic ligands (L) chosen because of their various biological activities, exhibited signi cant antiproliferative activity against a range of cancer cell lines.[4,5,6] An alternative strategy, based on the development of kinetically inert ruthenium half-sandwich complexes as potent inhibitors of protein kinases, has led to complexes exhibiting high cytotoxicity against the HCT-116 cell line.[7] Ru(II)–arene complexes have been incorporated into multinuclear systems and assessed for their anticancer activity. Our approach was to develop dinuclear Ru(II)– arene compounds linked together through the arene ligand in order to retain the core coordination environment around ruthenium as in the original RAPTA series to avoid signi cantly perturbing the coordination mode of these dinuclear complexes with potential biological targets

Results and discussion

Evaluation of in vitro anticancer activity

Conclusions