Research paperAnticancer, antifungal and antibacterial potential of bis(β-ketoiminato)ruthenium(II) carbonyl complexes
Section snippets
Synthesis of β-ketoiminato ruthenium(II) complexes
By treating a functionalised β-ketoiminate ligand (2 eq.), with triethylamine (2 eq.) and ruthenium(III) chloride trihydrate (1 eq.), whilst heating to reflux for 6 h in ethoxyethanol (~100 eq.), we attempted to synthesise ruthenium bis(β-ketoiminato)ruthenium(II) chloride complexes, [Cl(solv)(L)2Ru] or [Cl2(L)2Ru]+. However, from the reaction mixture the ruthenium dicarbonyl complexes 1–16 (Scheme 1) were isolated. This synthesis is characterised by the reduction of ruthenium in the metal
Analysis of β-ketoiminato ruthenium(II) complexes
Complexes 1–16 have been fully characterised by infrared spectroscopy, 1H, 13C{1H}, COSY and HMQC spectroscopy, mass spectrometry, elemental analysis and single crystal X-ray crystallography where appropriate. All complexes show the characteristic CO stretches between 1900 and 2100 cm−1, which are consistent with other reported ruthenium carbonyls (Fig. S1 and Table S6) [28]. 1H NMR spectroscopy was used to follow the progress of the reaction, with the loss of the β-ketoiminate ligand NH being
Chemosensitivity assays under normoxic conditions
The cytotoxicity values of complexes 1–16 were evaluated against human pancreatic carcinoma (MIA PaCa-2), human colon carcinoma (HCT116 p53+/+) and normal human retinal pigment epithelial cells (ARPE-19). All of the results highlight these complexes are either non-toxic or only moderately cytotoxic, therefore structure activity relationships cannot be fully determined (Table 1). There is a slight trend observed, whereby the para mono-substituted halide complexes 3 (4′-F), 6 (4′-Cl) and 8
Chemosensitivity assays under hypoxic conditions
Due to the abnormal vascularity and microenvironment of solid tumours, the use of chemotherapy and radiation cancer treatments becomes difficult, as tumour cells are often resistant to therapy [34]. An advantage of some inorganic complexes is the ability of the metal and/or redox active ligands to be activated in low oxygen (reducing) conditions, therefore, we have tested the moderately active complex 4 and cisplatin after 96 h incubation with the HCT116 p53+/+ cell line at an O2 concentraion
Stability studies in aqueous media
In order to address the stability of the complexes in aqueous conditions, initial samples were set up in 10% DMSO:90% H2O or D2O to analyse both the UV-vis and NMR spectra [38], however the complexes precipitate out of solution at such high water content (Figs. 5A and 5B). Samples were then made up at varying concentrations of water, and found to only remain in solution at 10% H2O. 1H NMR samples were prepared in 90% d3-acetonitrile:10% D2O to give a final concentration of 8 mg mL−1, and
Antifungal and antibacterial properties of β-ketoiminato ruthenium(II) complexes
To date there have been few reports on the use of ruthenium complexes as anti-fungal agents [39], though activities against Aspergillus flavus and fusarium species have been reported for ruthenium Schiff base complexes. In collaboration with the CO-ADD (Community for Antimicrobial Drug Discovery, The University of Queensland, Australia), we have evaluated the antifungal activities of complexes 1–16 against Candida albicans (C. albicans) and Cryptococcus neoformans var. grubii (C. neoformans)
Conclusions
In this study we have introduced a range of new bis(β-ketoiminato) ruthenium(II) carbonyl complexes which are formed from an unusual reaction pathway. We are currently conducting mechanistic work on the understanding of these reactions and products. The complexes were screened for their anticancer, antimicrobial and antifungal activities, whereby the different position of the substituents on the β-diketoiminate ligand has a significant effect on the complexes’ activity. Though the anticancer
Notes and references
The authors would like to thank Dr Markus Zegke for crystallography support, Mr. Stephen Boyer for conducting elemental analysis (London Metropolitan University Elemental Analysis Service) and Dr Stuart Warriner for providing mass spectrometry analysis (University of Leeds). They would also like to acknowledge Dr Samantha Shepherd (University of Huddersfield) for cell culture training. The work was kindly supported by the Schlumberger Foundation-Faculty for the Future. The authors also kindly
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors would like to thank the universities of Leeds, Huddersfield and Bradford for internal financial support.
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