Coordination chemistry of the antitumor metallocene molybdocene dichloride with biological ligands

Abstract

The relative affinity of molybdocene dichloride (Cp(2)MoCl(2)) for the thiol, amino, carboxylate, phosphate(O) and heterocyclic(N) donor ligands present in amino acids and nucleotides, has been studied in aqueous solutions at pH 2-7, using (1)H, (13)C and (31)P NMR spectroscopy. Molybdocene dichloride forms the highly water soluble, air-stable complexes Cp(2)Mo(Cys)(2) and Cp(2)Mo(GS)(2) with cysteine and glutathione respectively, via coordination of the deprotonated thiol groups. While coordination to the imidazole nitrogen in histidine was observed, no evidence for coordination of the amino or carboxylate groups in the amino acids cysteine, histidine, alanine or lysine to Cp(2)MoCl(2) was detected. Competition experiments with dAMP, ribose monophosphate and histidine showed preferential coordination to the cysteine thiol over the phosphate(O) and heterocyclic(N) groups. Cp(2)Mo(Cys)(2) is stable in the presence of excess dAMP or ribose monophosphate and Cys displaces coordinated histidine, dAMP or ribose monophosphate to give Cp(2)Mo(Cys)(2). These results provide further evidence against interaction with DNA as the key interaction that is related to the antitumor activity of molybdocene dichloride. The implications of these results for the biological activity of the antitumor metallocene and the likely species formed in vivo are discussed.