Antitumour metallocenes: Structure-activity studies and interactions with biomolecules

The metallocene dihalides are a relatively new class of small, hydrophobic organometallic anticancer agents that exhibit antitumour properties against numerous cell lines including leukemias P388 and L1210, colon 38 and Lewis lung carcinomas, B16 melanoma, solid and fluid Ehrlich ascites tumours and several human colon and lung carcinomas transplanted into athymic mice. Ti tanocene dichloride 1 has been the most widely studied metallocene and the drug is currently in phase II clinical trials. Formation of metallocene-DNA complexes has been implicated in the mechanism of antitumour properties of the metallocenes, as both titanocene dichloride 1 and vanadocene dichlorid e 2 inhibit DNA and RNA synthesis, and titanium and vanadium accumulate in nucleic acid-rich regions of tumour cells. However, in contrast to the well characterized platinum-based anticancer drugs, the active species responsi ble for antitumour activity in vivo has not been identified and the mechani sm whereby irreparable DNA damage and/or structural modification of DNA or other cellular targets occurs is poorly understood. This review will focus on recent studies that have been carried out in orde r to identify the biologically active species and more fully understand the molecular level mechanism of action of the metallocene dihalides. Studies with nucleotides, oligonucleotides, DNA and proteins including topoisomeras es, protein kinase C and transferrin have provided important insight into p otential cellular transport mechanisms and the interaction of metallocenes with biomolecular targets. New structure activity studies including the des ign of hydrolytically stable metallocenes and the preparation of highly wat er soluble amino acid analogues have not led to improved anticancer activit y of titanocene dichloride 1. The vastly different chemical and hydrolytic stability of each of the metallocenes points to a unique mechanism of actio n of each metallocene in vivo.