Interactions of molybdocene dichloride with histidine- and methionine-containing peptides

The reaction behavior of the antitumor active metallocene dihalide Cp2MoCl2 (Cp = η5-cyclopentadienyl) towards AcHis, AcHis(1-Me), AcHis(3-Me), His-Gly, AcHis-Gly-His, AcMet, Gly-Met-Gly and cyclo-Met-Met has been studied in solution at 2.5 ⩽ pD ⩽ 7.4 by using 1H NMR spectroscopy. The histidine-containing substrates were found to bind the Cp2Mo2+ unit through the terminal carboxylate group or through the N1 nitrogen of the imidazole ring, depending on the pD value. At physiological pH, coordination takes place exclusively at the imidazole ring with the percentage of Cp2Mo2+-His adducts in 1:1 mixtures being about 70%. By contrast, the thioether group in the side chain of methionine has a very low affinity for the Cp2Mo2+ group. Monodentate S-coordination could not be detected. For AcMet, binding through the carboxylate group was observed as the only coordination mode, while in the case of Gly-Met-Gly Mo–S interaction occurs in combination with carboxylate coordination leading to a S,O-macrochelate in low yield. Coordination to methionine peptides only takes place at pD ⩽ 6, while at physiological pH interactions with the weak donor sites are not observed due to predominating dimerization of [Cp2Mo(H2O)(OH)]+ to [Cp2Mo(μ-OH)2MoCp2]2+. At c(Cl−) = 100 mM competitive Cl− coordination reduces the amount of carboxylate and S,O-coordination significantly, while imidazole coordination is not affected.