Relationship between DNA-reactivity and cytostatic effect of two novel bile acid-platinum derivatives, Bamet-UD2 and Bamet-D3

Background and Aims: Several platinum(ll)-bile acid derivatives, named Bame ts, have been previously synthesized. Their ability to interact with DNA, t heir cytostatic activity and their liver organotropic properties have been characterized. Two new compounds of this family, with particular structural proper-ties have been developed. Bamet-UD2 was formed by two ursodeoxychol ic acid moieties bound by the carboxylate groups to cisplatin. In contrast, in Bamet-D3, glycine and a polyamine were used as tandem spacer elements t o separate a cholic acid moiety from the platinum(ll) atom. The aim of this work was to evaluate how these changes affect the ability of these compoun ds to intel act with DNA and reduce tumour cell growth. Materials and Metho ds: Drug reactivity with DNA was determined by changes in the electrophoret ic mobility of the pUC18 plasmid rest and by the ethidium bromide (EthBr) d isplacement assay. Cytostatic activity was measured against two mouse-deriv ed cell lines fi om lymphocytic leukemia (L1210) and sal coma (S-180-II). R esults: Bamet-UD2, and more markedly Bamet-D3, induced changes in the elect rophoretic mobility of pUC18, suggesting the formation of DNA-drug interact ions. Bamet-UD2 displaced EthBr from its binding to DNA. This effect was st ronger in the case of Bamet-D3. Scatchard plots revealed that pre-incubatio n with both Bamet-UD2 and Bamet-D3 decreased the number of DNA sites availa ble and their ability to bind EthBr. In spite of the enhanced DNA-reactivit y of Bamet-D3, its ability to reduce tumour cell growth was much weaker tha n that of Bamet-UD2, which was seen to exert a very strong cytostatic effec t. Conclusion: Although the distance between the platinum atom and the bile acid moiety affects the in vitro Bamet reactivity with DNA, other factors determine the overall cytostatic activity of these compounds.