Interactions of the Triaquatricarbonylrhenium(I) Cation with Nucleotides and Other N-Donor Ligands

Abstract

Transition metal centers possessing an octahedral geometry are useful for understanding the natural role of metal ions in biology. Complexes based on such metals might improve upon the widely used square planar Pt(II) anticancer drug cisplatin, cis-[Pt(NH3)2Cl2]. The octahedral triaquatricarbonylrhenium(I) cation, fac-[Re(CO)3(H2O)3]+, has been shown to possess anticancer activity. Furthermore, Re(I) complexes containing unstable rhenium isotopes have found utility as radiodiagnostic and radiotherapeutic agents. Thus, this work focuses on elucidating the fundamental coordination chemistry of fac-[Re(CO)3(H2O)3]+. Adducts formed in reactions of nucleoside mono-, di-, and triphosphates with fac-[Re(CO)3(H2O)3]OTf are examined by using a combination of 1D and 2D multinuclear nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD) spectroscopy, and molecular modeling techniques. Mixtures containing fac-[Re(CO)3(H2O)3]+ and nucleotides attain equilibrium, in contrast to cisplatin, and the nature of the adduct formed depends on the number of phosphate groups and the base present. Nucleoside di- and triphosphate adducts consist of diastereomers having distinct, sharp NMR signals, thus allowing accurate measurement of 1H and 31P NMR chemical shifts and coupling constants. Re(I) coordination at N7 is observed for all adducts with guanine bases, and the reactions proceed to near completion. {N7,Pb} and {N7,Pb,Pg} macrochelates are formed for 5¢-GDP and 5¢-GTP, respectively, but only N7 binding is observed for 5¢-GMP. The lack of Pa binding for 5¢-GTP indicates that formation of an N7–Re–Pa chelate ring is sterically unfavorable. When methionine and 5¢-GMP are allowed to compete for fac-[Re(CO)3(H2O)3]+, the N7-bound Re/5¢-GMP 1:1 adduct is the kinetic product, while the S-bound Re/methionine adduct is thermodynamically favored, a result opposite to that typically found for cisplatin. No base interaction was noted for adducts with uridine bases, and these reactions were incomplete at equilibrium. fac-[Re(CO)3(H2O)3]+ forms {Pa,Pb} and {Pa,Pb,Pg} phosphato chelates with 5¢-UDP and 5¢-UTP, respectively, but no significant reaction occurred with 5¢-UMP. Notably, fac-[Re(CO)3(H2O)3]+ forms both an {N7,Pb,Pg} macrochelate and a {Pa,Pb,Pg} phosphato chelate with 5¢-ATP, suggesting that the fac-[Re(CO)3]+ core could provide a model for the kinetically labile biorelevant [Mg(ATP)] complex. These results offer hope that (radio)pharmaceuticals based on Re(I) could be developed with lower toxicity than drugs based on Pt(II).