Comprehensive 2D ¹ H 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 solutions has been studied by means of optical and 2D NMR (COSY, TOCSY, and EXSY) techniques. These results indicate that a 1:1 Yb(3+)-drug complex (1) is the predominant complex at a metal-to-ligand ratio <10 with slightly higher proton activities, e.g., approximately pH 4-5 in an aqueous solution. In the presence of a base, a 1:2 (2) or 1:3 (3) Yb(3+)-drug complex can be formed. In addition, a 2:1 complex (4) is formed when the metal-to-drug ratio is >25. These Yb(3+)-drug complexes undergo slow chemical exchange with each other relative to the NMR time scale. Therefore, 1D and 2D magnetization transfer experiments can be utilized for the assignment of the isotropically shifted signals arising from the drug nuclei in the various paramagnetic complexes. The spin-lattice (T(1)) relaxation times and solution magnetic susceptibilities of these Yb(3+)-drug complexes confirmed the binding of the metal ion to 11,12-beta-ketophenolate in all the complexes (except the second Yb(3+) in the 2:1 complex which binds to the 5,6-beta-ketophenolate). Several other lanthanide(III) ions Pr(3+), Eu(3+), and Dy(3+) show similar binding properties to daunomycin based on optical and NMR studies. The binding of Yb(3+) to daunomycin has a profound effect on the reduction potential of the drug, showing a decrease in the potential by 150 mV upon addition of 1 equiv of Yb(3+) to the drug solution. This observation indicates that metal ions must play a significant role in the action of these family of drugs in vivo.