Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents—the cytotoxic antiprimary tumour compound [(η6-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η6-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]—and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel ‘atom-to-cell’ approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.
Chelating neutral (N,O) and cationic (N,N) first- and second-generation ruthenium(II) arene metallodendrimers based on poly(propyleneimine) dendrimer scaffolds were obtained from dinuclear arene ruthenium precursors by reactions with salicylaldimine and iminopyridyl dendritic ligands, respectively. The N,N cationic complexes were isolated as hexafluorophosphate salts and were characterised by NMR and IR spectroscopy, and MALDI-TOF mass spectrometry. Related mononuclear complexes were obtained in a similar manner and their molecular structures have been determined by X-ray diffraction analysis. The cytotoxicities of the mono- and multinuclear complexes were established using A2780 and A2780cisR human ovarian carcinoma cancer cell lines.
Ruthenium(II) arene compounds have been modified with
the naphthalimide group, tethered via the arene ligand, i.e. {dichloro[η6-N-(phenylalkyl)(4-dimethylamino)-1,8-naphthalimide](pta)ruthenium(II)}
(alkyl = methyl, ethyl, propyl, pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane),
or via an imidazole group, i.e. {dichloro(η6-arene)(N-[3-(imidazol-1-yl)propyl]-1,8-naphthalimide)ruthenium(II)}
(arene = p-cymene, toluene). All the compounds are
reasonably cytotoxic (ca. 2–49 μM) toward cancer cells,
and the arene-linked compounds also display selectivity in that they
are less cytotoxic toward model healthy cells. Mechanistic studies
show that the ruthenium center does not readily react with DNA but
preferentially binds to proteins. In contrast, the naphthalimide group
is a strong DNA intercalator, and combined, the complexes might be
expected to simultaneously cross-link DNA and proteins.
A ruthenium(II)-arene complex with a perfluoroalkyl-ligand was found to display remarkable selectivity toward cancer cells. IC50 values on several cancer cell lines are in the range of 25-45 μM, and no cytotoxic effect was observed on nontumorigenic (HEK-293) cells at concentrations up to 500 μM (the maximum concentration tested). Consequently, this complex was used as the basis for the development of a number of related derivatives, which were screened in cancerous and noncancerous cell lines. The lead compound was then evaluated in vivo for antiangiogenic activity in the CAM model and in a xenografted ovarian carcinoma tumor (A2780) grown on the CAM. A 90% reduction in the tumor growth was observed.
Application of mild hyperthermia can increase the cytotoxicity of anticancer drugs in tumour cells. In this report, we describe low molecular weight thermoactive ruthenium-based drugs with fluorous chains that are selectively triggered by mild hyperthermia. The organometallic complexes were prepared, characterized, and evaluated for their in vitro cytotoxicity against a panel of human cancer cell lines and non-cancerous immortalized cells. The compounds show considerable chemo-thermal selectivity towards cancer cells (ca. 5 mM versus >500 mM for healthy cells) for the compound with the longest fluorous chain.
Tridentate cycloplatinated thiosemicarbazone complexes
have been
prepared from a biologically significant ligand, 3,4-dichloroacetophenone
thiosemicarbazone (1). The tetranuclear complex 2 was prepared by reaction of the ligand with K2[PtCl4]. Two mononuclear (3 and 4) and two dinuclear (5 and 6) complexes
were isolated upon cleavage of the Pt–Sbridging bonds
of the tetranuclear complex 2 with the appropriate phosphane
ligand. Each complex was characterized using various analytical and
spectroscopic techniques, and the molecular structures of 2–4 were also elucidated. The in vitro antiparasitic activities of these complexes against Plasmodium falciparum strains (D10 (chloroquine sensitive)
and Dd2 (chloroquine resistant)) and Trichomonas vaginalis have been determined. Preliminary studies into their potential plasmodial
target in the form of β-hematin formation inhibition assays
were also completed. Preliminary results suggest that ligand 1 and complex 3 do not hinder formation of β-hematin.
The antiproliferative activity of the complexes against the cisplatin-senstive
A2780 and cisplatin-resistant A2780cisR human ovarian cancer cell
lines has been evaluated. The complexes were found to exhibit moderate
to weak inhibitory activities.
Following the identification of [Ru(η(6)-p-cymene)Cl2(1H,1H,2H,2H-perfluorodecyl-3-(pyridin-3-yl)propanoate)], a ruthenium(II)-arene complex with a perfluoroalkyl-modified ligand that displays remarkable in vitro cancer cell selectivity, a series of structurally related compounds were designed. In the new derivatives, the p-cymene ring and/or the chloride ligands are substituted by other ligands to modulate the steric bulk or aquation kinetics. The new compounds were evaluated in both in vitro (cytotoxicity and migration assays) and in vivo (chicken chorioallantoic membrane) models and were found to exhibit potent antivascular effects.
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