Compelling evidence for a stepwise mechanism of the alkaline cyclisation of uridine 3'-phosphate esters

A Bronsted graph with a convex break at pK(a)(Lg)= 12.58 provides compelling evidence for an intermediate in the alkaline cyclisation of uridine 3'-phosphate esters. The transient pentacoordinated oxyphosphorane dianion intermediate collapses to reactant and cyclic uridine 2',3'-monophosphate faster than it can pseudo-rotate and isomerise to the 2'-isomer.     

Hydrolytic reactions of thymidine 5'-o-phenyl-N-alkylphosphoramidates, models of nucleoside 5'-monophosphate prodrugs

To obtain detailed data on the kinetics of hydrolytic reactions of triester-like nucleoside 5'-O-aryl-N-alkylphosphoramidates, potential prodrugs of antiviral nucleoside monophosphates, the hydrolysis of diastereomeric (Rp/Sp) thymidine 5'-{O-phenyl-N-[(1S)-2-oxo-2-methoxy-1-methylethyl]phosphoramidate} (3), a phosphoramidate derived from the methyl ester of L-alanine, has been followed by reversed-phase HPLC over the range from Ho=0 to pH 8 at 90 degrees C. According to the time-dependent product distributions, the hydrolysis of 3 proceeds at pH<4 by two parallel routes, namely by nucleophilic displacement of the alaninyl ester moiety by a water molecule and by hydrolysis of the carboxylic ester linkage that allows intramolecular attack of the carboxy group on the phosphorus atom, thereby resulting in the departure of either thymidine or phenol without marked accumulation of any intermediates. Both routes represent about half of the overall disappearance of 3. The departure of phenol eventually leads to the formation of thymidine 5'-phosphate. At pH>5, the predominant reaction is hydrolysis of the carboxylic ester linkage followed by intramolecular displacement of a phenoxide ion by the carboxylate ion and hydrolysis of the resulting cyclic mixed anhydride into an acyclic diester-like thymidine 5'-phosphoramidate. The latter product accumulated quantitatively without any indication of further decomposition. Hydroxide-ion-catalyzed P--OPh bond cleavage of the starting material 3 occurred as a side reaction. Comparative measurements with thymidine 5'-{N-[(1S)-2-oxo-2-methoxy-1-methylethyl]phosphoramidate} (4) revealed that, under acidic conditions, this diester-like compound is hydrolyzed by P--N bond cleavage three orders of magnitude more rapidly than the triester-like 3. At pH>5, the stability order is reversed, with 3 being hydrolyzed six times as rapidly as 4. Mechanisms of the partial reactions are discussed.     

Hydrolysis of Phosphodiester Bonds within RNA Hairpin Loops in Buffer Solutions: the Effect of Secondary Structure on the Inherent Reactivity of RNA Phosphodiester Bonds

The hydrolysis of phosphodiester bonds of chimeric 2′-O-methyloligoribonucleotides was studied in buffer solutions. Pseudo-first-order rate constants for cleavage of phosphodiester bonds within hairpin loops were calculated and compared with those for cleavage of phosphodiester bonds within double-stranded stems and linear single-stranded oligonucleotides. No large differences in reactivity were observed: some of the hairpin structures studied were slightly less and others slightly more reactive than the linear reference. These results suggest that phosphodiester bonds within small hairpin loops are conformationally free to cleave by an in-line mechanism, but also that the secondary structure may influence the reactivity of phosphodiester bonds.     

Ethylene‐Norbornene Terpolymerization with 5‐Vinyl‐2‐norbornene Using Single‐Site Catalysts

The incorporation of 5‐vinyl‐2‐norbornene (VNB) into ethylene‐norbornene copolymer was investigated with catalysts [Ph₂C(Fluo)(Cp)]ZrCl₂ ( 1 ), rac‐[Et(Ind)₂]ZrCl₂ ( 2 ), and [Me₂Si(Me₄Cp)^tBuN]TiCl₂ ( 3 ) in the presence of MAO by terpolymerizing different amounts of 5‐vinyl‐2‐norbornene with constant amounts of ethylene and norbornene at 60°C. The highest cycloolefin incorporations and highest activity in terpolymerizations were achieved with 1 . The distribution of the monomers in the terpolymer chain was determined by NMR spectroscopy. As confirmed by XRD and DSC analysis, catalysts 1 and 3 produced amorphous terpolymer, whereas 2 yielded terpolymer with crystalline fragments of long ethylene sequences. When compared with poly‐(ethylene‐co‐norbornene), VNB increased both the glass transition temperatures and molar masses of terpolymers produced with the constrained geometry catalyst whereas decreased those for the metallocenes.     

Continuous learning methods in two-buyer pricing problem

This paper presents continuous learning methods in a monopoly pricing problem where the firm has uncertainty about the buyers’ preferences. The firm designs a menu of quality-price bundles and adjusts them using only local information about the buyers’ preferences. The learning methods define different paths, and we compare how much profit the firm makes on these paths, how long it takes to learn the optimal tariff, and how the buyers’ utilities change during the learning period. We also present a way to compute the optimal path in terms of discounted profit with dynamic programming and complete information. Numerical examples show that the optimal path may involve jumps where the buyer types switch from one bundle to another, and this is a property which is difficult to include in the learning methods. The learning methods have, however, the benefit that they can be generalized to pricing problems with many buyers types and qualities.     

3-Acetyloxy-2-cyano-2-(alkylaminocarbamoyl)propyl groups as biodegradable protecting groups of nucleoside 5´-mono-phosphates

Thymidine 5′-bis[3-acetyloxy-2-cyano-2-(2-phenylethylcarbamoyl)propyl]phosphate (1) has been prepared and the removal of phosphate protecting groups by hog liver carboxyesterase (HLE) at pH 7.5 and 37 °C has been followed by HPLC. The first detectable intermediates are the (R(P))- and (S(P))-diastereomers of the monodeacetylated triester 14, which subsequently undergo concurrent retro-aldol condensation to diester 4 and enzyme-catalyzed hydrolysis to the fully deacetylated triester 15. The former pathway predominates, representing 90% of the overall breakdown of 14. The diester 4 undergoes the enzymatic deacetylation 700 times less readily than the triester, but gives finally thymidine 5′-monophosphate as the desired main product. To elucidate the potential toxicity of the electrophilic 2-cyano-N-(2-phenylethyl)acrylamideby-product 17 released upon the deprotection, the hydrolysis of 1 has also been studied in the presence of glutathione (GSH).     

Preparation, characterization and application of a stationary chromatographic phase from a new (+)-tartaric acid derivative

The preparation, characterization and application of a new stationary phase derived from 1,4-cyclohexanedione and diethyl (+)-tartrate are described. A suitable TADDOL for immobilization has been synthesized and grafted to a γ-mercaptopropylsilylated silica gel. The resulting modified stationary phase has been characterized and its ability to separate enantiomers has been studied. While the free TADDOL in solution was able to resolve a range of enantiomers, the resolving properties were lost on immobilization. Solid state ¹³C CPMAS NMR of the new stationary phase was used to explain the lack of stereoselective recognition.     

Collection and behaviour of radon progenies on thin Mylar foils

Thin Mylar foils are often used to protect detectors from contamination. However, these foils can be electrostatically charged, possibly leading to their contamination with airborne radon progenies. In the present work, the collection and behaviour of radon progenies on Mylar foils was investigated in detail using alpha spectrometry. The radon progenies collection rate of a small Mylar foil (3 cm²) is equivalent to an air sampler with a flow rate of approximately 0.1 m³/h. It was demonstrated that such contamination may jeopardise the validity of the entire analysis if not interpreted correctly.     

Bis(5‐tert‐butyl‐2‐hydroxy‐3‐methylbenzyl)(6‐hydroxyhexyl)ammonium chloride monohydrate,an anion receptor complex

In the title compound, C₃₀H₄₈NO₃⁺·Cl⁻·H₂O, the cation acts with a water molecule as a chloride ion receptor. The chloride ion forms three strong intramolecular hydrogen bonds. The water molecule forms both an intramolecular bridge between one phenol H atom and the chloride ion, and an intermolecular link to the aliphatic alcohol O atom. Weak intermolecular C—H...Cl and C—H ...O hydrogen bonds provide additional packing interactions.     

140La/140Ba ratio dating of a nuclear release

In May 2010, air sampling stations in South Korea, Japan and the Russian Federation detected different unstable xenon isotopes and their progenies attached to aerosol particles. The origin of these fission products remains unclear. Previous studies have suggested that a possible reason for these observations is a nuclear test performed in North Korea in May 2010. In the present paper, preliminary spectra recorded at 2 h intervals at the particulate sampling station in Okinawa, Japan are analysed with rigorous mathematical methods. Based on the activity ratios of the ¹⁴⁰Xe progenies ¹⁴⁰Ba and ¹⁴⁰La in a sudden release scenario, the analysis provides an estimate of 12 May 16:00 (UTC) for the release date of the nuclear debris in the form of ¹⁴⁰Xe. The 95 % uncertainty limits for the release date are 11 May 9:00–13 May 13:00 (UTC). The result is very sensitive to the coincidence correction factor of the measurement setup and a larger uncertainty interval cannot be excluded. A continuous release scenario could also explain the data, possibly referring to a leak in a running nuclear reactor either on shore or in a vessel. No studies were made on the attribution of the observations to a release site. However, our conclusion is that fresh nuclear debris has been detected in East Asia, and further studies are required in an international forum to reanalyse the data. Of particular importance for the time-zero analysis is the a posteriori calibration of the Okinawa station with a ¹⁴⁰Ba sample to resolve the uncertainty related to the coincidence correction and other factors.