Acid–base and metal ion binding properties of 2-thiocytidine in aqueous solution

Abstract

The thionucleoside 2-thiocytidine (C2S) occurs in nature in transfer RNAs; it receives attention in diverse fields like drug research and nanotechnology. By potentiometric pH titrations we measured the acidity constants of H(C2S) + + (pK a = 4.24). This moderate effect of about 0.8 pK units contrasts with the strong acidification of about 4 pK units of the (C4)NH 2 group in C2S (pK a = 12.65) compared with Cyd (pK a & 16.7); the reason for this result is that the amino-thione tautomer, which dominates for the neutral C2S molecule, is transformed upon deprotonation into the imino-thioate form with the negative charge largely located on the sulfur. In the M(C2S) 2+ complexes the (C2)S group is the primary binding site rather than N3 as is the case in the M(Cyd) 2+ complexes, though owing to chelate formation N3 is to some extent still involved in metal ion binding. Similarly, in the Zn(C2S-H) + and Cd(C2S-H) + complexes the main metal ion binding site is the (C2)S -unit (formation degree above 99.99% compared with that of N3). However, again a large degree of chelate formation with N3 must be surmised for the M(C2S-H) + species in accord with previous solid-state studies of related ligands. Upon metal ion binding, the deprotonation of the (C4)NH 2 group (pK a = 12.65) is dramatically acidified (pK a & 3), confirming the very high stability of the M(C2S-H) + complexes. To conclude, the hydrogen-bonding and metal ion complex forming capabilities of C2S differ strongly from those of its parent Cyd; this must have consequences for the properties of those RNAs which contain this thionucleoside.Keywords Acidity constants Á Isomeric equilibria Á RNAs with thionucleosides Á Stability constants Á Tautomeric equilibria Species written without a charge either do not carry one or represent the species in general (i.e., independent of their protonation degree); which of the two possibilities applies is always clear from the context. A formula like (C2S-H) + means that the ligand has lost a proton and it is to be read as C2S minus H + .

Synthesis of a peptide nucleic acid with a novel 1‐methyl‐6‐mercaptopurine base

“…1-Methyl-6-mercaptopurine (3) could be alkylated with ethyl bromoacetate in DMF by first generating the anion with NaH at room temperature. This procedure yielded one product which was identified as the expected, ethyl (1-methyl-6-mercaptopurin-9-yl)acetate (5). Alkaline hydrolysis of 5 followed by neutralization with cation exchange resin afforded the target base 6 in quantitative yield (Scheme 1).…”

“…Moreover, PNAs may also find various interesting applications in chemistry and technology, e.g. as electrochemical biosensors, and in optical data storage [5][6][7]. In PNA the deoxyribose phosphate backbone of the nucleic acid is replaced by a chiral or achiral pseudopeptide backbone and nucleobases are attached via methylene carbonyl linkers (Figure 1).…”

Connectivity patterns and rotamer states of nucleobases determine acid–base properties of metalated purine quartets

“…While in the first case pK a values typically dropped by 1-2 units, e.g., for N1H in guanine complexes with Pt II at the N7 position [24,45], larger shifts of several units were seen in complexes in which the metalated nucleobase had adopted a rare tautomer structure [29,[40][41][42][43][44]46]. However, even in the absence of any tautomerization process, the pK a shift can be dramatic (9-10 units), provided that two metal ions coordinate simultaneously and the anion formed is favorably stabilized by an intramolecular interaction with a second nucleobase [47].…”

Characterization of Complexes of Nucleoside-5′-Phosphorothioate Analogues with Zinc Ions

“…The "thiophilic" character of Zn 2+ is also exemplified in Zn 2+ -2-thiocytidine complex with log K of 2.53, being ∼2.3 log units more stable than the parent complex, Zn 2+ -cytidine. 12 Yet, the Zn 2+ vs Mg 2+ -selectivity of phosphorothioate analogues was barely reported. Stability constants of several nucleoside 5′-phosphorthioate analogues with Mg 2+ and Cd 2+ were determined by 31 P NMR, 13,14 indicating that Cd 2+ affinity to ATP-α-S, ATP-β-S, and ADP-α-S is higher than that of Mg 2+ by ∼0.5−1.4 log units (log K 4.47, 4.04, and 3.66 vs 4.92, 5.44, and 4.95, respectively).…”

“…Moreover, Zn 2+ has affinity for thiolate second only to Cu 2+ throughout biological systems. , For instance, Zn 2+ -dithiothreitol complex exhibits log K of 11.06, where a 7-membered ring is formed because of Zn 2+ coordination with two thiol groups. The “thiophilic” character of Zn 2+ is also exemplified in Zn 2+ -2-thiocytidine complex with log K of 2.53, being ∼2.3 log units more stable than the parent complex, Zn 2+ -cytidine …”