Structural analysis of a de novo designed metalloprotein

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Journal of Inorganic Biochemistry 96 (2003)

Towards the Determination of the Mechanism of Antitumour Activity of Molybdocene Dichloride Jennv B Waern, School of Chemistry, The University of Sydney,Australia Carolyn T Dillon, School of Chemistry, The University of Sydney,Australia Margaret M Harding, School of Chemistry, The University of Sydney,Australia The biological chemistry of the metallocene dihalides, CpzMCl, (M = Ti, MO, V, Nb), has attracted significant interest since the antitumour activity of these organometallic complexes was first reported in 1979 [ 11. Titanocene dichloride is the most studied ofthe metallocenes, and is currently in phase II clinical trials. Titanium has been shown to accumulate in nucleic acid rich regions of the tumour cell, and CpzTiCl, forms adducts with both nucleic acid components and bulk DNA. While the other antitumour metallocenes have been less studied, current evidence strongly suggests that the different metallocene complexes interact differently with cellular components, and therefore probably have different antitumour mechanisms of action [2]. Although molybdocene dichloride coordinates to nucleotides [3], molybdocene-oligonucleotide adducts are not formed under physiological conditions [4], suggesting that this metallocene is likely to have an alternative cellular target to DNA. Extensive studies on the interaction and competitive coordination of molybdocene dichloride with nucleic acid components, glutathione and amino acids have been performed. Molybdocene dichloride preferentially coordinates to thiols over amino and carboxylate groups or nucleotides, indicating that formation of molybdocene-thiol complexes is related to their ~O&y&xH3 biological activity. The stable and highly water soluble derivatives Cp,Mo(Cys), (1) and Cp,Mo(GSH), (2) have been isolated and & ,$f&/ooH & ,,..,s fully characterised. d& In parallel, studies have been performed to determine the %gb