Model Systems for Metal - DNA Interactions. With a Focus on Anticancer Active Platinum(II) Complexes

Abstract: Reactions of trans-dicyanodichloroaurate(III) trans-dibromodicyanoaurate(III), trans-diamminedichlorogold(III), cis-diammine(aqua)chloroplatinum(II), cis-ammineaqua-(cyclohexylamine)chloroplatinum(II), chloro(terpyridine)platinum(II) and chloro-(diethylenetriaminepalldium(II) with dimethyl sulfide, thionucleosides, thionucleotides and thione- and guanine-containing 17-mer oligonucleotides have been investigated by use of conventional and high-pressure stopped-flow spectrophotometry and HPLC technique as a function of ionic strength, pH, temperature and pressure in aqueous solutions. The mechanism and rate of oxidation of dimethyl sulfide by gold(III) complexes depends on the concentration of free halide. High halide concentration leads to reduction of trans-dicyano(dimethylsulfide)halidegold(III) (halide = Cl or Br) through attack by free dimethyl sulfide on co-ordinated halide. Low halide concentration allows formation of trans-dicyanobisdimethylsulfidegold(III), which is reduced intermolecularly with assistance from a water molecule. Oxidation of the thioether is much more rapid at high chloride concentration, suggesting that the extra-cellular environment strongly favours this type of reaction in vivo. The use of DNA containing thiones in the form of 4-thiouridine or 6-thioinosine allowed for evaluation of the specific interaction of this site with metal complexes by UV/Vis detection technique. The nucleophilicity of both thiones was found to be better than that of guanine-N7. The pH dependence for 2.0 < pH < 5.0 was found to be due mainly to changes of the co-ordination environment of the metal centre. Studies of the reaction between monomers and gold(III) complexes revealed that the kinetic influence from a single phosphate group is small, only capable of compensating for the increased steric bulk when reacting with a cationic metal complex. The reactivity of the thione units change after incorporation into a poly d(T) oligonucleotide. The reactivity with anionic Au(III) complexes was decreased, whereas the reactions of cationic complexes of Au(III), Pd(II) and Pt(II) all were found to be accelerated in the DNA environment. The magnitude of rate enhancement was strongly dependent on the ionic strength of the reaction medium. Reactions of the oligomers were found to be most favoured at low ionic strength, with a maximum rate enhancement of a factor of 56 observed at ionic strength = 1.0 mM for the reaction of cis-ammineaqua-(cyclohexylamine)chloroplatinum(II) with a 17-mer poly d(T) oligonucleotide containing a single thiouridine in the middle. Further, for similarly sized oligomers the rate enhancement were found to depend both on the type of binding site and its position along the oligomer. Both these observations suggest an influence from the local surrounding on the kinetics. The obtained series for platination of the middle position: phosphorothioate > thiouridine > thioinosine > G-N7, indicates a dependence on the distance from the phosphate backbone. The reaction profile for the platination of a single G-N7 that is moved along the oligomer suggests an additional influence from electrostatic, polyelectrolyte-like accumulation of cations. Inspection of the activation parameters (enthalpy, entropy, volume) shows that the difference in reactivity between the monomers and oligomers is largely due to contributions from the activation entropies. For the latter type of reactions, the entropy values are substantially more positive, which is interpreted as a result of pre-association of the cationic metal complex onto the oligomer, and concomitant release of monovalent cations such as sodium and potassium from the surface. The similar type of reaction characteristics, here demonstrated for the cations with an inherent reactivity spanning 4 orders of magnitude, suggest a common reaction mechanism for these structural analogs of anticancer active Pt(II) complexes, where preassociation is followed by rapid reorganisation and/or migration of the metal reagent on the surface of the oligomer prior to the rate determining reaction.