SOLUTION STUDIES OF THE ANTITUMOR COMPLEX DICHLORO 1,2-PROPYLENDIAMINETETRAACETATE RUTHENIUM-(III) AND OF ITS INTERACTIONS WITH PROTEINS

A mixed complex of ruthenium (III) with 1,2-propylendiaminetetraacetat e (PDTA) and chloride - RAP hereafter - has been found to exhibit favo rable anticancer properties in vivo. To get some insight into the poss ible mechanism of action of this ruthenium (III) complex, its solution behavior and reactivity with proteins were investigated through absor ption, circular dichroism and H-1 NMR spectroscopies. Under physiologi cal conditions RAP slowly looses the two coordinated chlorine atoms to produce a number of ruthenium (III) reactive species; a description o f the distribution of these species on the dependence of pH has been o btained through H-1 NMR studies of the hyperfine shifted signals. Rema rkably, through the different solution conditions employed in this stu dy, the ruthenium ion always remains in the 3(+) oxidation state and t he PDTA ligand is always bound to the metal. Upon reaction with albumi n, apotransferrin or diferric transferrin, at a 1:1 ratio, RAP rapidly binds to these proteins to produce substantially equivalent and relat ively stable adducts. This behavior is tentatively interpreted in term s of a tight interaction between RAP and surface residues of these pro teins. The implications of these findings for the biological action of this novel ruthenium (III) compound are discussed. (C) 1998 Elsevier Science Inc. All rights reserved.