Acid–base and metal ion-binding properties of thiopyrimidine derivatives

摘要: Abstract The thionucleoside 2-thiocytidine (C2S) as well the thiouridines (US) occur in Nature, especially transfer RNAs, and they also receive attention diverse fields like nanotechnology drug research. If (C2)O cytidine (Cyd) is replaced by (C2)S to give thio analogue C2S, release of H+ from (N3)H H(C2S)+ (pKa = 3.44) facilitated somewhat [H(Cyd)+; pKa = 4.24], yet, deprotonation (C4)NH2 group much more affected: pKa decreases ca. 16.7 Cyd 12.65 C2S. This because amino-thione tautomer dominating neutral transfers into imino-thioate form, which has charge largely localized on (C2)S−. As a consequence, M(C2S)2+ species (M2+ = Zn2+ or Cd2+) very easily their deprotonated M(C2S − H)+ forms. reaction extremely M2+coordination at (C2)S− occurs already pH slightly above 3. It shown that M2+ coordination dominates than 99% both complexes; structures, including chelate formation with participation N3, are evaluated. In 2-thiouridine (U2S), 4-thiouridine (U4S), 2,4-dithiouridine (U2S4S), (N3)H, compared Urd (pKa = 9.18), 1 2 pK units, being (C)S sites; this leads (U4S − H)− (U2S4S − H)− reduction Cu(II) Cu(I), transforming thiolate disulfide. Cu(U2S − H)+ stable, most likely due steric constraints inhibiting disulfide formation. stability M(US − H)+ complexes Ni2+, Cu2+ Cd2+ enhanced about 1.3 2 log units corresponding uridinate complexes. properties biologically relevant Zn(US − H)+ expected be between those Ni2+ Cd2+. relatively high affinity sites for these reflected 5′-monophosphate (U2SMP2−) (U4SMP2−) complexes, located thiouracil residue only traces coordinated phosphate group. N3-deprotonated Cu[(U2S − H)MP]− anti conformer partly turned syn one allowing thus degree 60% macrochelate formed pattern seems hold Cd[(U2S − H)MP]−, though lower. No detected Ni[(U2S − H)MP]−, Ni[(U4S − H)MP]− Cd[(U4S − H)MP]−. reasons indicated patterns discussed, biological implications summarized results, regard tRNAs.