Enhancing the Methyl-Donor Activity of Methylcobalamin by Covalent Attachment of DNA

The preparation of a covalent DNA conjugate of vitamin B12 by means of heterogeneous solid‐phase synthesis is reported. The cyano‐corrinoid made available, dipotassium Coβ‐cyanocobalamin‐(3″→2′),(3″→5′)‐bis‐2″‐deoxythymidyl‐3″‐ate (K2‐4), was cleanly methylated at the Co center by electrosynthetic means. Aqueous solutions of the resulting organometallic DNAB12 conjugate K2‐5 exhibited spectroscopic properties indicative of significant weakening of the axial (CoN) bond, together with a 25‐times higher basicity relative to Coβ‐methylcobalamin (2). Methyl‐transfer equilibria of pH‐neutral aqueous solutions of K2‐5 and cob(I)alamin (K‐7) on one side, and of cob(I)alamin‐(3″→2′),(3″→5′)‐bis‐2″‐deoxythymidyl‐3″‐ate (K3‐8) and methylcobalamin (2) on the other, were studied at room temperature (Scheme 3). The NMR‐derived data provided an equilibrium constant of ca. 0.3. Activation of K2‐5 for ion of its Co‐bound Me group by a nucleophile (such as cob(I)alamin) was, thus, indicated.