Comparison of the Surprising Metal-Ion-Binding Properties of 5-and 6-Uracilmethylphosphonate (5Umpa(2-) and 6Umpa(2-)) in Aqueous Solution and Crystal Structures of the Dimethyl and Di(isopropyl) Esters of H-2(6Umpa)

摘要

5- and 6-Uracilmethylphosphonate (5Umpa(2-) and 6Umpa(2-)) as acyclic nucleotide analogues are in the focus of anticancer and antiviral research. Connected metabolic reactions involve metal ions; therefore, we determined the stability constants of M(Umpa) complexes (M2+ = Mg2+, Ca2+, Mn2+, Co2+, Cu2+, Zn2+, or Cd2+). However, the coordination chemistry of these Umpa species is also of interest in its own right, for example, the phosphonate-coordinated M2+ interacts with (C4)O to form seven-membered chelates with 5Umpa(2-), thus leading to intramolecular equilibria between open (op) and closed (cl) isomers. No such interaction occurs with 6Umpa(2-). In both M(Umpa) series deprotonation of the uracil residue leads to the formation of M(Umpa-H)(-) complexes at higher pH values. Their stability was evaluated by taking into account the fact that the uracilate residue can bind metal ions to give M-2(Umpa-H)(+) species. This has led to two further important insights: I)In M(6Umpa-H)(cl)(-) the H+ is released from (NI)H, giving rise to six-membered chelates (degrees of formation of ca. 90 to 99.9% with Mn2+, Co2+, Cu2+, Zn2+, or Cd2+). 2) In M(5Umpa-H)(cl)(-) the (N3)H is deprotonated, leading to a higher stability of the seven-membered chelates involving (C4)O (even Mg2+ and Ca2+ chelates are formed up to approximate to 50%). In both instances the M(Umpa-H)(op)(-) species led to the formation of M-2(UMP-H)(+) complexes that have one M2+ at the phosphonate and one at the (N3)(-) (plus carbonyl) site; this proves that nucleotides can bind metal ions independently at the phosphate and the nucleobase residues. X-ray structural analyses of 6Umpa derivatives show that in diesters the phosphonate group is turned away from the uracil residue, whereas in H-2(6Umpa) the orientation is such that upon deprotonation in aqueous solution a strong hydrogen bond is formed between (Nl)H and PO32-; replacement of the hydro gen with M2+ gives the M(6Umpa-H)(cl)(-) chelates mentioned.