title: Comparison of the surprising metal-ion-binding properties of 5- and 6-uracilmethylphosphonate (5Umpa2- and 6Umpa2-) in aqueous solution and crystal structures of the dimethyl and di(isopropyl) esters of H2(6Umpa).
abstract: 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 (M(2+)=Mg(2+), Ca(2+), Mn(2+), Co(2+), Cu(2+), Zn(2+), or Cd(2+)). However, the coordination chemistry of these Umpa species is also of interest in its own right, for example, the phosphonate-coordinated M(2+) 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: 1) In M(6Umpa-H)-cl the H(+) is released from (N1)H, giving rise to six-membered chelates (degrees of formation of ca. 90 to 99.9 % with Mn(2+), Co(2+), Cu(2+), Zn(2+), or Cd(2+)). 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 Mg(2+) and Ca(2+) chelates are formed up to approximately 50 %). In both instances the M(Umpa-H)-op species led to the formation of M(2)(Umpa-H)(+) complexes that have one M(2+) 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 (N1)H and PO(3) (2-); replacement of the hydro gen with M(2+) gives the M(6Umpa-H)-cl chelates mentioned.
authors.affiliation: Institute of Inorganic Chemistry, University of Zürich, 8057 Zürich, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Freisinger
authors.forename: Rolf
authors.initials: R
authors.lastname: Griesser
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lippert
authors.forename: Cristóbal F
authors.initials: CF
authors.lastname: Moreno-Luque
authors.forename: Juan
authors.initials: J
authors.lastname: Niclós-Gutiérrez
authors.forename: Justyn
authors.initials: J
authors.lastname: Ochocki
authors.forename: Bert P
authors.initials: BP
authors.lastname: Operschall
authors.forename: Helmut
authors.initials: H
authors.lastname: Sigel
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004355:Drug Stability; D004952:Esters / Q000737:chemistry*; D008958:Models, Molecular; D013816:Thermodynamics; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: C535037:5-uracilmethylphosphonate; C535038:6-uracilmethylphosphonate; D000970:Antineoplastic Agents; D004952:Esters; D014867:Water; D014498:Uracil