Although cisplatin is a widely used anticancer drug, its use has also been limited due to the presence of various side effects and the problemt of drug resistance. With the aim of reducing the side effects and widening spectrum of activity, thousands of cisplatin analogues have been prepared by changing the nature of leaving groups and carrier ligands. Although it has been possible to reduce the side effects, only a limited change in spectrum of activity has been achieved. Thus, currently much research efforts are directed in designing new platinum compounds that would violate classical structure-activity requirements of cisplatin in one way or another, with the idea that the difference in nature of interaction with the DNA may translate into an altered spectrum of activity. The target compounds of the present study are of the forms: [PtL3Cl]Cl (type 1) and PtL2Cl2 (type 2) where L= planaramine. Type 1 compounds can only form monofunctional adducts with DNA whereas type 2 compounds can form interstrand bifunctional adducts. The compounds (specially type 1) can undergo stacking interaction with nucleobases in the DNA and altered H-bonding. Because of the ionic nature of the compounds, type 1 compounds are expected to cross the cell membrane only by carrier-mediated transport and can be excellent substrates for organic cation transporters (OCT).
MTT reduction assay was used to determine activity of the compounds against a number of human ovarian cancer tumour models. Elemental analyses and spectral studies including IR, mass, 1H NMR and UV-visible spectrophotometry. Gel electrophoresis was used to investigate the interaction of the targeted compounds with genomic and non-genomic DNAs.
Type 2 compounds are found to be significantly more active than type 1 compounds. The results also show that the reduction inactivity in going from the parent to the resistant cell lines is less pronounced for the designed compounds than cisplatin so that they have lower resistance factors.
Designed rule-breaker platinum compounds differ greatly in activity, illustrating structure-activity relationship.