Bipyrimidine ruthenium(II) arene complexes: structure, reactivity and cytotoxicity

Autoři: Betanzos-Lara, S., Novakova, O., Deeth, RJ., Pizarro, AM., Clarkson, GJ., Liskova, B., Brabec, V., Sadler, PJ., Habtemariam, A.
Rok: 2012


The synthesis and characterization of complexes [(eta(6)-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 [(eta(6)-p-cym)Ru(bpm)I][PF6], [(eta(6)-bip)Ru(bpm)Cl][PF6], [(eta(6)-bip)Ru(bpm)I][PF6] and [(eta(6)-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 Ru-II 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 [(eta(6)-p-cym)Ru(bpm)Cl][PF6], [(eta(6)-p-cym)Ru(bpm)Br][PF6], [(eta(6)-p-cym)Ru(bpm)I][PF6], [(eta(6)-bip)Ru(bpm)Cl][PF6], [(eta(6)-bip)Ru(bpm)Br][PF6] and [(eta(6)-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 a parts per thousand 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 [(eta(6)-p-cym)Ru(bpm)Cl][PF6], [(eta(6)-hmb)Ru(bpm)Cl](+), [(eta(6)-ind)Ru(bpm)Cl](+), [(eta(6)-thn)Ru(bpm)Cl](+), [(eta(6)-p-cym)Ru(phen)Cl](+) and [(eta(6)-p-cym)Ru(bathophen)Cl](+) in aqueous solution at 310 K. The X-ray crystal structure of the guanine complex [(eta(6)-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 [(eta(6)-p-cym)Ru(bpm)Cl][PF6] and [(eta(6)-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.