COMPREHENSIVE 2D H-1-NMR STUDIES OF PARAMAGNETIC LANTHANIDE(III) COMPLEXES OF ANTHRACYCLINE ANTITUMOR ANTIBIOTICS

The binding of several lanthanide(III) ions to anthracycline antitumor antibiotics daunomycin and adriamycin in methanol and aqueous solutio ns has been studied by means of optical and 2D NMR (COSY, TOCSY, and E XSY) techniques. These results indicate that a 1:1 Yb3+-drug complex ( 1) is the predominant complex at a metal-to-ligand ratio <10 with slig htly higher proton activities, e.g., similar to pH 4-5 in an aqueous s olution. Ln the presence of a base, a 1:2 (2) or 1:3 (3) Yb3+-drug com plex can be formed. In addition, a 2:1 complex (4) is formed when the metal-to-drug ratio is >25. These Yb3+-drug complexes undergo slow che mical exchange with each other relative to the NMR time scale. Therefo re, 1D and 2D magnetization transfer experiments can be utilized for t he assignment of the isotropically shifted signals arising from the dr ug nuclei in the various paramagnetic complexes. The spin-lattice (T-1 ) relaxation times and solution magnetic susceptibilities of these Yb3 +-drug complexes confirmed the binding of the metal ion to 11,12-beta- ketophenolate in all the complexes (except the second Yb3+ in the 2:1 complex which binds to the 5,6-beta-ketophenolate). Several other lant hanide(III) ions Pr3+, Eu3+, and Dy3+ show similar binding properties to daunomycin based on optical and NMR studies. The binding of Yb3+ to daunomycin has a profound effect on the reduction potential of the dr ug, showing a decrease in the potential by 150 mV upon addition of 1 e quiv of Yb3+ to the drug solution. This observation indicates that met al ions must play a significant role in the action of these family of drugs in vivo.