Bioorganometallic chemistry of molybdocene dichloride

The study of molybdocene dichloride and related metallocenes has been dominated by their remarkable catalytic properties in organic synthesis and polymer chemistry. Interest in the aqueous, bioorganometallic chemistry of metallocene dihalides has stemmed from the potent antitumor properties of titanocene dichloride, including results from human clinical trials. This review will summarize key results reported in the last decade on the biological chemistry of molybdocene dichloride. The effect of concentration, pH and ionic strength on the rates of hydrolysis of both the cyclopentadienyl and halide ligands have established that the positively charged monoaquated species Cp ₂Mo(OH)(OH₂)⁺, in equilibrium with the dipositively charged dimer Cp₂Mo(μ-OH)₂MoCp ₂, is present under physiological conditions. Systematic studies of the coordination chemistry of Cp₂MoCl₂ with nucleobases, nucleotides, single-stranded and double-stranded oligonucleotides, and calf-thymus DNA have shown that while simultaneous phosphate(O) and heterocyclic(N) adducts are formed with nucleotides, negligible interaction with DNA occurs under physiological conditions. In contrast, Cp₂MoCl ₂ forms strong, non-labile complexes with deprotonated thiols in amino acids. Molybdocene dichloride is able to catalyse the hydrolysis of activated phosphate esters under physiological conditions, but hydrolysis of unactivated phosphodiesters is only significant at pH 4. Limited antitumor activity results, inhibition studies with protein kinase C and topoisomerase II, structure-activity and cell-uptake studies have provided some insight into possible mechanisms of antitumor action.