fac-[Re(CO)3(H2O)3]+ nucleoside monophosphate adducts investigated in aqueous solution by multinuclear NMR spectroscopy

The fac-[Re(CO)(3)(H2O)(3)](+) cation, the putative DNA-binding species accounting for the biological activity of related Re( I) complexes, binds reversibly to N7 of 6-oxopurine nucleotide monophosphates (NMPs), in contrast to Pt( II) anticancer drugs. A relatively high amount of NMP is needed to convert all of the fac-[Re(CO)(3)(H2O)(3)](+) to adducts. The Re/nucleotide 1:1 adduct forms more rapidly and builds up to a higher concentration for guanosine 5'-monophosphate (5'-GMP) and inosine 5'-monophosphate (5'-IMP) than for the respective 3'-monophosphates (3'-GMP and 3'-IMP). These results are attributable to the 5'-positioning of the 5'-NMP phosphate group that allows it to approach the metal inner sphere for more favorable cation electrostatic and aqua ligand H-bonding interactions, both in the initial productive ion pair encounter complexes and in the N7-bound 1: 1 adducts. A higher reactivity of 5'-GMP over 3'-GMP is known for cisplatin. In contrast, more Re/nucleotide 1: 2 adduct was formed by 3'-GMP (and 3'-IMP) than by 5'-GMP (and 5'-IMP). Because the 3'-phosphate group cannot closely approach the metal inner coordination sphere, the greater stability for the 3'-GMP 1:2 adduct reflects the more favorable G N1H-phosphate interligand GMP-GMP interactions for 3'-GMP vs 5'-GMP (G) guanine base derivative). This type of interaction is known for platinum adducts. In 1:2 adducts the bound nucleotides are inequivalent, prompting us to perform mixed 5'-GMP/3'-GMP experiments, leading to the observation of major (M) and minor (m) mixed Re/5'-GMP/3'-GMP 1: 1:1 adducts. The order of abundance at equilibrium in a typical experiment was M > bis 3'-GMP > m >= bis 5'-GMP. This stability order was rationalized by invoking the phosphate interactions described above. When methionine and 5'-GMP were allowed to compete for fac- [ Re( CO)(3)(H2O)(3)](+), the Re/5'-GMP 1:1 adduct was the kinetic product and the S-bound Re/methionine adduct was the thermodynamic product, a result opposite to that typically found for cisplatin.