Strong, Rapid Binding of a Platinum Complex to Thymine and Uracil Under Physiological Conditions

摘要

All four DNA bases adenine (A), cytosine (C), guanine (G), and thymine (T) (uracil, U, in RNA) are known to be capable of binding to metal ions through their ring N atoms and exo-cyclic N and O atoms. The major site of attack by platinum am(m)ine anticancer complexes is the N7 atom of guanine, which is readily accessible in the major groove of duplex DNA and is the strongest electron donor of the four bases, especially when situated next to another guanine residue. Thus, over 90% of Pt is found in intrastrand G G and A G cross-links. The N3 atom of thymine should provide a strong binding site for Pt but has a high pK_a value (ca. 10), and is usually inaccessible in double-stranded DNA due to involvement in A.T base pairs. Therefore cross-links involving thymine are not observed. Even when the N3 atom of thymine is exposed in single strands of DNA or in thymine derivatives, reactions with Pt am(m)ine complexes are usually very slow. It is of interest therefore to examine new methods of attaining kinetic control over attack by Pt on thymine bases. We report here the unusual ability of a cytotoxic platinum complex to bind strongly and rapidly to the N3 atom of thymine (and uracil) under physiological conditions.