Comprehensive 2D ¹H NMR Studies of Paramagnetic Lanthanide(III) Complexes of Anthracycline Antitumor Antibiotics

Xiangdong Wei and Li-June Ming*
Department of Chemistry and Institute for Biomolecular Science
University of South Florida, Tampa, Florida 33620-5250

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Synopsis
    Several paramagnetic lanthanide(III) complexes of the anthracycline antitumor antibiotics, daunomycin and adriamycin (see structures), have been prepared under several different conditions.  The isotropically shifted ¹H NMR spectrum of a 1:1 Yb³⁺-daunomycin complex (1) has been completely assigned, from which its configuration in solution can be determined.  These complexes with different stoichiometries 1:2 (2), 1:3 (3), and 2:1 (4) can be prepared under different proton and metal concentrations, and have been characterized by using EXSY technique.  These Yb³⁺-anthracycline complexes are used as model systems for further understanding of the binding of anthracycline antibiotics with alkaline earth metal and transition metal ions.  These studies may shed light on the effect of metal ions on the action of these quinone-containing drugs.
 

 

Abstract
    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 Yb³⁺-drug complex (1) is the predominant complex at a metal to ligand ratio <10 with slightly higher proton activities, e.g., ~pH 4-5 in an aqueous solution.  In the presence of a base, 1:2 (2) or 1:3  (3) Yb³⁺-drug complex 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 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 (T1) relaxation times and solution magnetic susceptibilities of these Yb³⁺-drug complexes confirmed the binding of the metal ion to 11,12-a-ketophenolate in all the complexes (except the second Yb³⁺ in the 2:1 complex which binds to the 5,6-a-ketophenolate).  Several other lanthanide(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 drug, showing a decrease in the potential by 150 mV upon addition of 1 equivalent Yb³⁺ 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.
 
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