Abstract
The synthesis and characterization of complexes [(η6-arene)Ru(N,N′)X][PF6], where arene is para-cymene (p-cym), biphenyl (bip), ethyl benzoate (etb), hexamethylbenzene (hmb), indane (ind) or 1,2,3,4-tetrahydronaphthalene (thn), N,N′ is 2,2′-bipyrimidine (bpm) and X is Cl, Br or I, are reported, including the X-ray crystal structures of [(η6-p-cym)Ru(bpm)I][PF6], [(η6-bip)Ru(bpm)Cl][PF6], [(η6-bip)Ru(bpm)I][PF6] and [(η6-etb)Ru(bpm)Cl][PF6]. Complexes in which N,N′ is 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione or 4,7-diphenyl-1,10-phenanthroline (bathophen) were studied for comparison. The RuII arene complexes undergo ligand-exchange reactions in aqueous solution at 310 K; their half-lives for hydrolysis range from 14 to 715 min. Density functional theory calculations on [(η6-p-cym)Ru(bpm)Cl][PF6], [(η6-p-cym)Ru(bpm)Br][PF6], [(η6-p-cym)Ru(bpm)I][PF6], [(η6-bip)Ru(bpm)Cl][PF6], [(η6-bip)Ru(bpm)Br][PF6] and [(η6-bip)Ru(bpm)I][PF6] suggest that aquation occurs via an associative pathway and that the reaction is thermodynamically favourable when the leaving ligand is I > Br ≈ Cl. pK a* values for the aqua adducts of the complexes range from 6.9 to 7.32. A binding preference for 9-ethylguanine (9-EtG) compared with 9-ethyladenine (9-EtA) was observed for [(η6-p-cym)Ru(bpm)Cl][PF6], [(η6-hmb)Ru(bpm)Cl]+, [(η6-ind)Ru(bpm)Cl]+, [(η6-thn)Ru(bpm)Cl]+, [(η6-p-cym)Ru(phen)Cl]+ and [(η6-p-cym)Ru(bathophen)Cl]+ in aqueous solution at 310 K. The X-ray crystal structure of the guanine complex [(η6-p-cym)Ru(bpm)(9-EtG-N7)][PF6]2 shows multiple hydrogen bonding. Density functional theory calculations show that the 9-EtG adducts of all complexes are thermodynamically preferred compared with those of 9-EtA. However, the bmp complexes are inactive towards A2780 human ovarian cancer cells. Calf thymus DNA interactions for [(η6-p-cym)Ru(bpm)Cl][PF6] and [(η6-p-cym)Ru(phen)Cl][PF6] consist of weak coordinative, intercalative and monofunctional coordination. Binding to biomolecules such as glutathione may play a role in deactivating the bpm complexes.
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Acknowledgments
S.B.-L. thanks WPRS/ORSAS (UK) and CONACyT (Mexico) for funding a research studentship. B.L., O.N. and V.B. were supported by the Czech Science Foundation (grants P301/10/0598 and 301/09/H004). We also thank EDRF and AWM (Science City) and ERC (grant no. 247450) for funding, and Ivan Prokes and Lijiang Song and Philip Aston of the University of Warwick for their help with NMR and HR-MS instruments, respectively.
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Details of the preparation and characterization of all the complexes in this work. Crystallographic data for 3, 4, 6, 7 and 14; mass-to-charge ratios obtained from HR-MS spectra for the products of hydrolysis of RuII arene complexes 1–14; mass-to-charge ratios obtained from HR-MS spectra for the products of interactions of RuII arene complexes 1, 8–11 and 13 with 9-EtG; changes in CD and LD spectra of CT–DNA modified by RuII arene complexes 1 and 11; X-ray crystal structure of 4 showing a π-π stacking interaction; CH-π interaction in the crystal structure of 7; biswater-bridged interaction in the X-ray crystal structure of 14; 1H-1H NOESY NMR spectrum of 14 in D2O (aromatic region only); time evolution of the hydrolysis reactions of complexes 1–13; dependence of the absorbance during aquation of 1 at 310 K; 1H NMR spectra recorded during a pH* titration of a solution of the aqua adduct of complex 1; DFT-optimized geometry in the transition state during the hydrolysis reaction of the RuII arene cation 1; 1H NMR spectra of the reaction of 10 with 9-EtG in D2O at 310 K after 510 min; optimized geometries for the guanine and adenine adducts; kinetics of the binding of complexes 1 and 11 to CT–DNA; hydrolysis reaction of complex 1 in the presence of 100-fold excess of GSH followed by UV–vis spectroscopy.
X-ray crystallographic data for complexes 3, 6, 14, 4 and 7 are available as supporting information and have been deposited in the Cambridge Crystallographic Data Centre (CCDC) under accession numbers CCDC 872981, 872982, 872983, 872984 and 872985, respectively. Copies of the data can be obtained free of charge from the CCDC (12 Union Road, Cambridge CB2 1EZ, UK; Tel.: +44-1223-336408; Fax: +44-1223-336003; e-mail: deposit@ccdc.cam.ac.uk; website http://www.ccdc.cam.ac.uk/).
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Betanzos-Lara, S., Novakova, O., Deeth, R.J. et al. Bipyrimidine ruthenium(II) arene complexes: structure, reactivity and cytotoxicity. J Biol Inorg Chem 17, 1033–1051 (2012). https://doi.org/10.1007/s00775-012-0917-9
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DOI: https://doi.org/10.1007/s00775-012-0917-9