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

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 Xray 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.

Tripodal Half‐Sandwich Rhodium and Iridium Complexes Containing Sulfonate and Pyridinyl Entities as Antitumor Agents

“…Observation of these shifts of signals in the 1 H NMR spectrum have been previously reported and similar shifts have been observed for the interactions between other metal complexes and mononucleotides via the N7 site …”

Anticancer Potential of Diiron Vinyliminium Complexes

“…The interaction of selected diiron complexes with a variety of biomolecules was studied to give insights into their mechanism of action. The reactivity of [ 7 ]CF 3 SO 3 with a mononucleotide (guanosine 5′‐monophosphate, 5′‐GMP) and an oligonucleotide DNA model (14‐mer, 5′‐ATACATGGTACATA‐3′), which have been used as models for other metallodrugs, was evaluated. No significant interactions were observed between the mono‐ or oligonucleotide with [ 7 ] + .…”

“…The affinity of the diiron complexes to proteins was investigated using established peptide and protein models, that is, amyloid β‐protein (residues 1–16), ubiquitin and bovine serum albumin (BSA) . The interactions of [ 7 ]CF 3 SO 3 with amyloid β‐protein and ubiquitin were assessed using mass spectrometry.…”

Diversity in Gold Finger Structure Elucidated by Traveling‐Wave Ion Mobility Mass Spectrometry

“…TheI Ms pectra add significantly to our ability to designate specific structures,which may not even be possible from some solution studies.T othe best of our knowledge,this is the first demonstration that {AuF} species can exist in structurally distinct conformations,r epresenting an ovel use of IM in protein structure analysis complementary to other spectroscopic and X-ray techniques. [21] Furthermore,t he conformational diversity of cancer-associated mutations in the zinc-bound p53 tumor suppressor protein has been probed by ion-mobility mass spectrometry. [19,20] Ruthenium(II)peptide interactions studied by IM highlight the important role played by the ligand in determining the shape of the adduct formed.…”