Effect of the amine non‐leaving group on the structure and stability of DNA complexes with cis‐[Pt(R‐NH2)2(NO3)2]

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Abstract
The antitumor compound cis-[Pt(NH3)2Cl2] (cisplatin), conserves two ammine ligands during the reaction with its cellular target DNA. Modifications of these non-leaving groups change the antineoplastic properties of this compound and its genotoxic effects. It is therefore of interest to determine the influence of non-leaving groups on the structure and stability of DNA in vitro. We have investigated platinum-DNA adducts formed by cis-[Pt(R-NH2)2(NO3)2] (where R-NH2 = NH3, methylamine, cyclobutylamine, cyclopentylamine and cyclohexylamine) as a function of DNA binding. All compounds quantitatively reacted with DNA in less than 1 h at 37 degrees C. They formed bifunctional adducts with adjacent nucleotides judging from the displacement of the intercalating molecule ethidium bromide, ultraviolet absorption spectroscopy and circular dichroism. Substitution of a H on the NH3 ligand by alkyl groups dramatically destabilized the platinum-DNA complex. Thermal stability decreased progressively with an increasing number of carbon atoms, delta tm = -4.4 degrees C for 3 cyclohexylamine-platinum-DNA adducts/1000 nucleotides, conditions where cisplatin had no effect. DNA adducts with cyclobutylamine and cyclohexylamine ligands inhibited the hydrolysis of platinum-DNA complexes by S1 nuclease. Km for the digestion of DNA containing these lesions was 2.3 times greater than for cisplatin, indicating steric inhibition of enzyme-substrate complex formation. These results show that the non-leaving groups of substituted cis-Pt(II) compounds may destabilize DNA and interfere with protein-DNA interactions. These perturbations may have consequences for the genotoxic and antitumor activities of platinum compounds.

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