[Ru2(μ-O2CR)4L2]+ Complexes with Biologically Relevant Axial (L) and Equatorial Ligands (R)
Earlier studies in our lab have shown complexes of the form M3[Ru2(μ-O2CC6H4SO3)4L2] to be 5 times more cytotoxic toward multi-drug reistant CoLo 320DM cancer cell lines than to HeLa cells, opposite to the behaviour of cisplatin. The mode of action is thought to be axial binding of the diruthenium to the N(7) of the guanine or adenine bases on the DNA. While the strength of this primary donor bond can be tuned to some degree by varying the nature of the R group in the "[Ru2(μ-O2CR)4L2]" unit, secondary interactions, such as H-bonding between the bridging carboxylates and the amino or carbonyl groups on the adenine or guanine bases respectively and π-π interactions of aromatic functionalities incorporated into the carboxylate R groups, can also be extremely important in stabilizing the interaction of the metal complex with DNA.
We are currently investigating how the [Ru2(μ-O2CR)4L2]+ core interacts with biologically relevant equatorial and axial ligands, such as purines and pyrimidines, to assess primary (coordinative bond) and secondary (H-bond and π-π) interactions in order to further design complexes with useful cytotoxic properties. Three earlier publications began this work, and we found that the H-bonding interaction(s) between the carboxylate oxygen atoms and the CH and/or NH2 group(s) adjacent to the heterocyclic nitrogen, that is directly bound to the ruthenium, are very important in dictating the orientation of the purine or pyrimidine with respect to the [Ru2(μ-O2CR)4L2]+ unit. Varying the R group to incorporate naphthalene, anthracene, coumarin, and indole moieties will allow us to investigate any potential π-π stacking interactions (and hence potential intercalation into DNA). Exchange of the equatorial carboxylate to accommodate these new R groups is facile. The direct interaction with adenine and guanine will be studied by synthesizing the [Ru2(μ-O2CR)4(adenine)2]+ and [Ru2(μ -O2CR)4(guanine)2]+ adducts directly. Complexes to be tested for cytotoxicity will be prepared as water-soluble adducts by incorporating an appropriate counterion (SO42-, Cl-, etc).