Computational simulation of mechanism and isotope effects on acetal heterolysis as a model for glycoside hydrolysis

DFT calculations for the equilibrium isotope effect for deuterium substitution at the anomeric centre Cα in 2-(p-nitrophenoxy)tetrahydropyran with continuum solvation show significant variation in the range of relative permittivity 2 ≤ ε ≤ 10. One-dimensional scans of potential energy (with implicit solvation by water) or of free energy (from QM/MM potentials of mean force with explicit aqueous solvation with a hybrid AM1/OPLS method) for heterolysis of the bond between Cα and the nucleofuge do not show a transition state. A two-dimensional free-energy surface that considers also the distance between Cα and a nucleophilic water indicates a pre-association DN*ANint‡ mechanism with a transition state involving nucleophilic attack upon an ion-pair intermediate, and this is supported by good agreement between the mean values of the calculated and experimental α-D KIEs. However, the magnitudes of the standard deviations about the mean values for the making and breaking C–O bonds suggest that the transition state is rather plastic, with Cα–Onu≈2 ± 0.4 Å and Cα–Olg≈3 ± 0.5 Å. Not only is nucleophilic solvent assistance necessary, but there is also evidence for electrophilic assistance through specific hydrogen bonding to the nucleofuge.

Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals

Objective: Stable heavy isotopes of hydrogen, carbon, and other elements have been incorporated into drug molecules, largely as tracers for quantitation during the drug development process. Studies involving the human use of drugs labeled with deuterium suggest that these compounds may offer some advantages when compared with their nondeuterated counterparts. Deuteration has gained attention because of its potential to affect the pharmacokinetic and metabolic profiles of drugs. Deutetrabenazine (Austedo, Teva Pharmaceutical Industries, Ltd) is the first deuterated drug to receive Food and Drug Administration approval. This deuterated form of the drug tetrabenazine is indicated for the treatment of chorea associated with Huntington’s disease as well as tardive dyskinesia. Ongoing clinical trials suggest that a number of other deuterated compounds are being evaluated for the treatment of human diseases and not merely as research tools. Data Sources: A search of the MEDLINE (1946 to present) database was undertaken using the Ovid interface. The search was conducted using the heading deuterium and then limited to Administration & Dosage, Adverse Effects, Pharmacokinetics, Pharmacology, Poisoning, Therapeutic Use, and Toxicity. Study Selection and Data Extraction: All articles were reviewed and those with human information were included. Review articles were likewise interrogated for additional published human data. Conclusions: Deuterated compounds may, in some cases, offer advantages over nondeuterated forms, often through alterations in clearance. Deuteration may also redirect metabolic pathways in directions that reduce toxicities. The approval of additional deuterated compounds may soon follow. Clinicians will need to be familiar with the dosing, efficacy, potential side effects, and unique metabolic profiles of these new entities.

Small-angle neutron scattering measurements of δ-phase deuteride (hydride) precipitates in Zircaloy 4

Small-angle neutron scattering (SANS) measurements have been performed under ambient conditions to characterize deuteride (hydride) particles in Zircaloy 4, a fuel cladding material used in pressurized light-water nuclear reactors. Hydrogen pickup by the cladding leads to a rim structure in which large circumferential hydride plate-like particles preferentially form on the cooler water-side region of the cladding. Deuterium substitution has been used to increase the coherent response and decrease the incoherent background of the SANS measurements. Four bulk deuterium concentrations were investigated, approximately 100, 400, 500 and 1000 parts per million by weight (w.p.p.m.) deuterium, as well as a zero-deuterium-concentration reference sample. The net SANS response from the deuteride phase was determined at all concentration values after subtraction of the reference SANS response, which effectively subtracted the strong scattering from second-phase particles in as-received Zircaloy. The net SANS response consisted of strong Porod scattering from deuteride particles over the entire measured Q range (0.005–0.4 Å−1). The net SANS response was anisotropic at concentrations greater than 100 w.p.p.m. and required elliptical averaging analysis. A significant sample orientation effect on the intensity of the SANS response was observed, due to preferential alignment of deuteride particles. The effect of ex situ applied stress at elevated temperature on deuteride phase dissolution and reprecipitation was investigated; a weak effect was observed with SANS that could not be confirmed by optical microscopy.