Bond Order and Charge Localization in Nucleoside Phosphorothioates

Abstract

In the recent literature on nucleoside phosphorothioate anions the structural formulas show a double bond between phosphorus and sulfur and a single bond between phosphorus and oxygen with a negative charge localized on oxygen. However, a review of physical data on these compounds shows the reverse to be the case; that is, in phosphorothioate anions the P-S bond is a single bond with a negative charge localized on sulfur, while the P-O bond order for exocyclic and nonbridging oxygens is greater than 1, approaching 2 in O-alkyl phosphorothioate monoanions and O,O-dialkyl phosphorothioates. The P-O bond orders in phosphorothioate dianions and trianions approach 1 1/2 and 1 1/3, respectively, owing to delocalization of negative charge among two or three oxygens. These conclusions are based on bond lengths obtained from x-ray crystallographic data and electron diffraction, the magnitudes of the effects of 18O on the 31P-nuclear magnetic resonance chemical shifts of phosphorus in nucleoside [18O]phosphorothioates, the pH-dependence of 17O-NMR chemical shifts in [17O]phosphate and [17O]thiophosphate, the vibrational spectra of thiophosphate di- and trianions, and the pKa (dissociation constant) values for phosphoric and thiophosphoric acids.

Phosphorothioate oligonucleotides reduce mitochondrial outer membrane permeability to ADP

“…Compared with oxygen, the sulfur atom has less electronegativity, and its larger van der Waal's radius decreases its surface charge density, which may allow it to carry a full negative charge in solution. (12,14). The sulfur also lacks the ability to hydrogen bond with water, and so water dissociates more readily from the oligonucleotide.…”

Phosphorothioate cap analogs stabilize mRNA and increase translational efficiency in mammalian cells

“…Although sulfur substitution for oxygen is considered conservative because the van der Waals radius, P-S bond length (Liang and Allen 1987), and anionic character of parent and modified oligonucleotides are all very similar (Frey and Sammons 1985;Chang et al 1986), there are nonetheless important differences between phosphate and phosphorothioate groups, including the existence of diastereoisomers. Interestingly, these isomers can exhibit different sensitivities to nucleases.…”

Kinetic Isotope Effects for Alkaline Phosphatase Reactions: Implications for the Role of Active-Site Metal Ions in Catalysis

“…For simplicity, the P-S and P-O bonds of pNPPS are depicted with the same partial double bond character, although it is likely that the P-S bond has more single bond character than the P-O bonds. 43,83 Figure 2.…”