The influence of structure on the activity and toxicity of Pt anti-cancer drugs

The development and current status of the relationships between the structure of platinum based anti-cancer drugs and their biological activities are reviewed. The early structure-activity relationships contributed to the development of many other active compounds and to the development of the understanding of the mechanism of activity of this class of drugs. However, they may also have contributed to the focusing on a group of compounds that has yet to produce a major advance over cisplatin or carboplatin. The recent development of new highly active platinum based drugs that do not fit the structure-activity rules indicates the need for a reappraisal of these rules. Some new structure-activity relationships are emerging but we conclude that in general it is unlikely that widely applicable rules will be sustained or be useful. We also review the results of our recent work aimed at rationally probing the relationships between structure and activity. We describe studies aimed at determining why cisplatin does not bind to GpA sequences of duplex DNA and determining whether the GG interstrand adduct contributes to anti-cancer activity. Chiral probes of Pt/DNA interactions, cytotoxicity and other toxicities are also described. Stereoselective interactions between Pt complexes and DNA are described and the factors contributing to the stereoselectivity are discussed. (C) 1997 Elsevier Science S.A.