Cationic Interactions with Nucleic Acids With Focus on Anticancer Active Platinum(II) Complexes

University dissertation from Department of chemistry, biochemistry

Abstract: It is well documented that the antitumour activity of the Pt(II)-complex cisplatin, and similar anticancer active complexes, is a result of metalation of DNA, and thereby inhibition of cell proliferation. Since nucleic acids are polyanions at physiological pH, the rate of adduct formation with positively charged complex, as the hydrolyzed Pt(II) complexes studied in this work, is influenced by the ionic environment surrounding the polymer. Such effects have been investigated in different nucleic acid models. The type and concentration of bulk cations highly affect the reaction rate, e.g. divalent ions are more efficient in retarding the platination reaction than monovalent ions, due to the better neutralization of the phosphate charges. The rates of adduct formation between cis-[PtCl(NH3)(c-C6H11NH2)(OH2)]+ and a model with single-stranded oligonucleotides were found to decrease significantly in the presence of manganese(II) in comparison to magnesium(II). This is suggested to be a result of a direct interaction for manganese(II) with the platination site, G-N7. Furthermore, the reactivity was found to depend on the location of the target site within the oligomers, where the central position possessed the highest rate. The influence from the oligomeric length on the reaction rate with cis-[PtCl(NH3)(c-C6H11NH2)(OH2)]+ and d(TnGTn), where n = 4, 6, 8, 12, 16 and 24, was studied. A length-dependent rate enhancement was found up to n = 8, at low concentration of bulk cations. These results present evidence for the presence of a rate enhancing preassociation step in the reaction mechanism. Studies of addition of tri- and tetravalent polyamines to the platination reaction of single stranded oligomers and dsDNA were performed. Results varied on the bulk cation concentration and type of polyamine. The overall trend was a decrease in platination rate in the presence of polyamines. Polyamine competition with the platinum(II) complex for the condensation layer, including direct association with the platination site, was assumed to be responsible for the decreased platination rate. Platination of nucleic acids is known to induce structural distortions, resulting in duplex destabilization and higher rigidity of the structure. Both these effects were separately studied with two different RNA–models. An RNA oligonucleotide with a potential to adopt a pseudoknot structure, was platinated and found to be more stable towards intramolecular transesterification than the unmetalated one. This observation was interpreted as a result of higher rigidity of the whole molecule. The other model used was short duplex RNAs, with function as efficient siRNAs in a model system. Incorporation of oxaliplatin in the sense strand results in duplex destabilization, but with retained efficiency as siRNAs. This is promising for future studies of metalated siRNAs.

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