New Ruthenium tach Complexes as Water-Soluble Chemotherapy Agents

Ruthenium complexes are currently attracting much attention in the field of medicinal chemistry as they provide numerous properties which make them an appropriate candidate for drug design. Recently, a series of ruthenium tach complexes with extremely high in vitro activity and high solubility have been developed. Cis-1,3,5-triaminocyclohexane (tach) provides a hydrogen bond donor through amine groups, which aids both solubility and interaction with biomolecules.
The chemistry of the ruthenium tach complexes was developed in order to understand their activity in a biological environment. The parent compound, tach [2] was modified by the incorporation of a new functional group (benzyl) into the coordination sphere of the ligand and synthesis a new tach analogue, tachmb [3]. The coordination chemistry of [3] was performed with a range of different ruthenium precursors to yield [Ru(tachmb)(DMSO)Cl2] [5], [Ru(tachmb)(PPh3)Cl2] [7], and [Ru(tachmb)(dppb)Cl]Cl [9]. The anti-proliferative activity of the modified tach [3] and the complexes were evaluated with in vitro tests against A549 (human lung cancer) and A2780 (human ovarian cancer) cell lines. The activity of [3] showed mild activity in comparison to the non-toxic tach, [2]. Both complexes [7] and [9] showed high activity; in particular, the activity of [9] was found to exceed that of cisplatin in both cell lines.
Two new analogues of ruthenium tach complexes tagged with fluorescent ligands were synthesised and fully characterised, [Ru(tach)(FL-I)Cl]Cl [10] and [Ru(tach)(FL-II)Cl]Cl [13]. Two previously reported complexes were also prepared; one complex with high cytotoxic activity ([Ru(tach)(dppp)Cl]Cl, [11]) and one complex with light sensitive behaviour ([Ru(tach)(phen)(DMSO)], [12]). The interactions of these complexes with Calf Thymus DNA (CT-DNA) and bovine serum albumin (BSA) were examined spectrophotometrically. The results show intercalation behaviour of [10] and [12] towards DNA while complex [11] instead exhibits high binding affinity towards BSA. The cytotoxicity of the complexes indicates that proteins may be the potential biological targets of ruthenium tach anti-cancer drugs.