New ruthenium tach complexes as water-soluble chemotherapy agents

• Main Author: Arkawazi, Sham
• Other Authors: Lynam, Jason ; Walton, Paul
• Published: University of York 2017
• Subjects: 540
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.731573

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.