First-principles prediction of the pK(a)s of anti-inflammatory oxicams

The gas- and aqueous-phase acidities of a series of oxicams have been computed by combining M05-2X/6-311+G(3df,2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further carried out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomers are possible in each protonation state. The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the microscopic pK(a)s on both solution- and gas-phase equilibrium conformers, and these were combined to yield the macroscopic pK(a) values. Using the direct cycle of pK(a) calculation, the CPCM-UAKS model delivered reasonably accurate results with MAD ~ 1, whereas the SMD and COSMO-RS models' performance was less satisfactory with MAD ~ 3. Comparison with experiment also indicates that direct cycle calculations based on solution conformers generally deliver better accuracy. The proton exchange cycle affords further improvement for all solvent models through systematic error cancellation and therefore provides better reliability for the pK(a) prediction of compounds of these types. The latter approach has been applied to predict the pK(a)s of several recently synthesized oxicam derivatives.     

Context-dependent behavior of the enterocin iterative polyketide synthase; a new model for ketoreduction

Heterologous expression and mutagenesis of the enterocin type II polyketide synthase (PKS) system suggest for the first time that the association of an extended set of proteins and substrates is needed for the effective production of the enterocin-wailupemycin polyketides. In the absence of its endogenous ketoreductase (KR) EncD in either the enterocin producer "Streptomyces maritimus" or the engineered host S. lividans K4-114, the enterocin minimal PKS is unable to produce benzoate-primed polyketides, even when complemented with the homologous actinorhodin KR ActIII or with EncD active site mutants. These data suggest that the enterocin PKS requires EncD to serve a catalytic and not just a structural role in the functional PKS enzyme complex. This strongly implies that EncD reduces the polyketide chain during elongation rather than after its complete assembly, as suggested for most type II PKSs.     

Assessment of 4-nitrogenated benzyloxymethyl groups for 2'-hydroxyl protection in solid-phase RNA synthesis

The search for a 2'-OH protecting group that would impart ribonucleoside phosphoramidites with coupling kinetics and coupling efficiencies comparable to those of deoxyribonucleoside phosphoramidites led to an assessment of 2'-O-(4-nitrogenated benzyloxy)methyl groups through solid-phase RNA synthesis using phosphoramidites 2a-d, 12a, and 14a. These phosphoramidites exhibited rapid and efficient coupling properties. Particularly noteworthy is the cleavage of the 2'-O-[4-(N-methylamino)benzyloxy]methyl groups in 0.1 M AcOH, which led to U19dT within 15 min at 90 degrees C. [reaction: see text]     

Amine-directed intramolecular hydroacylation of alkenes and alkynes

Medium-ring heterocycles are prepared via an amine-directed, rhodium(I)-catalyzed intramolecular hydroacylation. The presence of an allyl substituent on the amine accelerates the reaction and increases product yields.     

Determination of Atrazine,Simazine, Alachlor,and Metolachlor in Surface Water Using Dispersive Pipette Extraction and Gas Chromatography–Mass Spectrometry

Four commonly found pesticides (alachlor, atrazine, metolachlor, and simazine) in surface water were determined using dispersive pipette extraction followed by gas chromatography–mass spectrometry. The rapid mixing and equilibrium between the dispersive pipette extraction adsorbent and water sample resulted in fast and efficient extraction. Using only 5?mL of water sample, the estimated time consumption for extraction of each sample was less than 5?min. Method validation was performed to evaluate accuracy, precision, linearity, the limits of detection, and the limits of quantitation. Average recovery of above 90% was obtained with relative standard deviations below 10%, which indicated good accuracy and precision of the dispersive pipette extraction method. Coefficients of determination were all above 0.9901 and showed good linearity. For the four pesticides studied using the current method, the limits of detection ranged from 7 to 40?ng?L^?1, and limits of quantitation were from 20 to 130?ng?L^?1. Method validation results supported the application of the current method for drinking water safety monitoring per National Primary Drinking Water Regulations established by the US Environmental Protection Agency. Water samples from Lake Lanier and Stone Mountain Lake (Georgia, USS) were analyzed with this method as a preliminary work for a larger scale drinking water quality study in the future. Trace amounts of simazine and atrazine were found in lake water samples, but both were below the regulation levels of the US Environmental Protection Agency.     

Synthesis,alkali metal picrate extraction,and alkali metal cation binding selectivities of some new cage‐annulated polyoxamacrocyclic crown ethers

Five new cage‐annulated crown ethers, i.e., 4a, 4b, 6b, 11a, and 11b, have been synthesized and their respective alkali metal picrate extraction profiles along with that of a previously synthesized host molecule, 6a, have been obtained. These results are compared with the corresponding results obtained for electrospray ionization mass spectrometric (ESI‐MS) measurements of relative binding selectivities displayed by the same hosts toward a series of alkali metal chlorides. Among the crown‐5 hosts studied, 6a displays enhanced avidity toward complexation with K⁺ picrate in liquid‐liquid extraction experiments. Among the three crown‐6 hosts, 4b proved to be the best alkali metal picrate extractant and displayed significant levels of avidity toward complexation with the larger alkali metal cations (i.e., K⁺, Rb⁺, and Cs⁺). The trends in the picrate extraction and the ESI‐MS results obtained herein show several notable similarities and some differences. The similarities generally stem from size‐selective binding properties that are intrinsic to the different cavity sizes of the cage‐annulated macrocycles, whereas the differences reflect the important influence of solvation effects on the binding properties of the macrocycles.     

Sortin1-hypersensitive mutants link vacuolar-trafficking defects and flavonoid metabolism in Arabidopsis vegetative tissues

Sortin1 is a chemical genetic-hit molecule that causes specific mislocalization of plant and yeast-soluble and membrane vacuolar markers. To better understand its mode of action, we designed a Sortin1-hypersensitive screen and identified several Sortin1-hypersensitive and flavonoid-defective mutants. Mechanistically, Sortin1 mimics the effect of the glutathione inhibitor buthionine sulfoximine and alters the vacuolar accumulation of flavonoids, likely blocking their transport through vacuole-localized ABC transporters. Structure-activity relationship studies conducted in Arabidopsis revealed the structural requirements for Sortin1 bioactivity and demonstrated that overlapping Sortin1 substructures can be used to discriminate between vacuolar-flavonoid accumulations and vacuolar-biogenesis defects. We conclude that Sortin1 is a valuable probe for dissecting novel links among flavonoid transport, vacuolar integrity, and the trafficking of vacuolar targeted cargoes in Arabidopsis.     

Dependence of collision‐induced dissociation energy on molecular degrees of freedom as a means to assess relative binding affinity in multivalent complexes

In collision‐induced dissociation mass spectrometry experiments, the collision energy required for dissociation linearly depends on the degrees of freedom in the precursor ion. The magnitude of the slope of this relationship previously has been shown to qualitatively correlate to the relative binding strength of a noncovalently bound, monovalent complex. The goal of the work presented here is to determine if a similar methodology can be applied for assessing relative binding strengths in multivalent species. We have tested the method on complexes formed from 18‐crown‐6 and a variety of protonated, primary alkylamines, [C_nH_2n+1NH₃]⁺ (n = 9, 12, 14, 16 and 18) and alkyldiamines, [H₃NC_nH_2nNH₃]²⁺ (n = 3, 5, 6, 9 and 12), and compared our results with dissociation energies calculated using density functional theory at the B3LYP/6‐31G* level. We found that the method correctly assessed the stronger crown ether/headgroup interaction in the two divalent species (1:1 and 2:1 complexes formed from the diaminoalkanes) compared with the weaker interaction in the monovalent species (1:1 complexes formed from mono‐aminoalkanes). However, the experimental method could not distinguish between the binding strengths of the two divalent complexes, perhaps because their calculated dissociation energies were quite similar. Our preliminary results suggest that this method could potentially be used for a quick and simple analysis of binding strengths in multivalent species if the binding strengths of the species are significantly different from one another. Copyright © 2011 John Wiley & Sons, Ltd.     

Efficient tetrahydropyranyl and tetrahydrofuranyl protection/deprotection of alcohols and phenols with Al(OTf)3 as catalyst

A simple and efficient method for the conversion of alcohols and phenols into their corresponding THP and THF ethers at room temperature has been developed using 1 mol % aluminium triflate as catalyst. The deprotection reaction in the presence of methanol using Al(OTf)₃ was equally successful and could be performed at ambient temperature in high yields.