Reaction force decomposition of activation barriers to elucidate solvent effects

The reaction force F(Rc) of a chemical or physical process is given by the negative derivative of the potential energy V(Rc) along the intrinsic reaction coordinate Rc. F(Rc) unambiguously and naturally divides the activation barrier in each direction into two contributions, one of which has been found to reflect preparative structural factors, Eact,prep, and the other corresponds to the first part of the transition to products, Eact,trans. We have analyzed F(Rc) for an SN2 substitution reaction in both the gas and aqueous phases. Although the overall forward and reverse activation barriers are significantly lowered by the solvent, the Eact,trans are very little affected. Thus the increased rates that are predicted for this process in aqueous solution can be attributed to the solvent facilitating the structural effects in the preparative stages, decreasing the Eact,prep. This example shows how the reaction force decomposition of activation barriers can help to elucidate the roles played by external factors, e.g., solvents.     

Hydrogen-bonded cubanes and ladder fragments by analogy with the inorganic solid state

By application of an analogy with the structures of alkali-metal phosphinimides, two hydrogen-bonded cubanes, [Ph(3)CNH(3)(+)X(-)](4) (X = Cl, Br), and one unprecedented four-rung ladder fragment, [Ph(3)CNH(3)(+)I(-)](4), have been prepared in the organic solid state.     

The single-crystal, basal face of ice I(h) investigated with sum frequency generation

Sum frequency generation spectroscopy has been used to investigate the hydrogen-bonded region of single-crystal, hexagonal ice in the temperature range of 113-178 K. The temperature and polarization dependences of the signal are used in conjunction with a recent theoretical model to suggest an interpretation of the bluest and reddest of the hydrogen-bonded peaks. The reddest feature is associated with strong hydrogen bonding; the dynamic polarizability of this feature is primarily parallel to the surface. It is assigned to a cooperative motion among the companion to the free-OH and four-coordinate oscillators hydrogen bonded to dangling lone-pair molecules on the surface. The bluest hydrogen-bonded feature is similarly assigned to a cooperative motion of the OH stretch of dangling lone-pair molecules and of four-coordinate molecules in the lower half bilayer that are hydrogen bonded to free-OH molecules. Reconstruction induced strain is present at as low as 113 K. These results provide a richer picture of the ice surface than has heretofore been possible.     

Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2

An efficient synthesis of 2-substituted O(4)-cyclohexylmethyl-5-nitroso-6-aminopyrimidines from 6-amino-2-mercaptopyrimidin-4-ol has been developed and used to prepare a range of derivatives for evaluation as inhibitors of cyclin-dependent kinase 2 (CDK2). The structure-activity relationships (SARs) are similar to those observed for the corresponding O(6)-cyclohexylmethoxypurine series with the 2-arylsulfonamide and 2-arylcarboxamide derivatives showing excellent potency. Two compounds, 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2-hydroxyethyl)benzenesulfonamide (7q) and 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7s), were the most potent with IC50 values of 0.7 +/- 0.1 and 0.8 +/- 0.0 nM against CDK2, respectively. The SARs determined in this study are discussed with reference to the crystal structure of 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7j) bound to phosphorylated CDK2/cyclin A.     

Regio- and enantioselective hydroamination of dienes by gold(i)/menthol cooperative catalysis

Alcohol is key: Regio- and enantioselective hydroamination of 1,3-dienes has been achieved with the dinuclear catalyst (R)-DTBM-SEGPHOS. The rate and selectivity of the reaction are enhanced by alcohol additives like menthol, which coordinates the cationic gold(I) to generate a Br?nsted acid that can participate in catalysis. Mbs=p-methoxybenzenesulfonyl.     

Quantifying heterogeneity and conformational dynamics from single molecule FRET of diffusing molecules: recurrence analysis of single particles (RASP)

Single molecule F?rster resonance energy transfer (FRET) experiments are a versatile method for investigating the conformational distributions and dynamics of biological macromolecules. In a common type of experiment, the fluorescence bursts from individual molecules freely diffusing in solution are detected as they pass through the observation volume of a confocal microscope. Correlation analysis of the fluorescence bursts shows that under typical experimental conditions, for time scales up to several tens of milliseconds, the probability for a molecule to return to the confocal volume is greater than the probability of a new molecule being detected. Here we present RASP (recurrence analysis of single particles), a method that is based on this recurrence behavior and allows us to significantly extend the information that can be extracted from single molecule FRET experiments. The number and peak shapes of subpopulations within the sample can be identified essentially in a model-free way by constructing recurrence FRET efficiency histograms. These are obtained by first selecting photon bursts from a small transfer efficiency range (initial bursts), and then building the FRET efficiency histogram only from bursts detected within a short time (the recurrence interval) after the initial bursts. Systematic variation of the recurrence interval allows the kinetics of interconversion between subpopulations to be determined on time scales from ~50 μs up to ~100 ms from equilibrium measurements. We demonstrate the applicability of the method on measurements of several peptides and proteins with different degrees of conformational heterogeneity and folding dynamics. The concepts presented here can be extended to other observables available from single molecule fluorescence experiments.     

Fungal cyclooligomer depsipeptides: from classical biochemistry to combinatorial biosynthesis

This review surveys the biological activities and the iterative and recursive biosynthetic mechanisms of fungal cyclooligomer depsipeptides, and their structural diversification by various combinatorial biosynthetic methods.     

Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors

The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a "proof-of-concept" for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A?nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibition of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity.     

Interfacial behavior of OEG-linear dendron monolayers: aggregation, nanostructuring, and electropolymerizability

We report on the interesting interfacial behavior of oligoethylene glycol or OEGylated linear dendron monolayers at the air-water interface as a function of (a) carbazole dendron generation, (b) the length of the OEG units, and (c) the surface pressure applied upon compression. Surface pressure-area isotherms, hysteresis studies, and isobaric creep measurement revealed a structure-property relationship consistent with the hydrophilic-lipophilic balance of a linear dendron with the OEG group serving as the surface anchor to the water subphase. AFM studies revealed that all the OEGylated carbazole dendrons self-assemble into spherical morphology at low surface pressures but form ribbonlike structures as the surface pressure is increased. This nanostructuring is primarily imparted by the increase in van der Waals forces with increasing amount of carbazole units per dendron generation on a hydrophilic mica surface. Further, electrochemical cross-linking of the carbazole molecules by cyclic voltammetery (CV) on doped Si wafer has enabled the formation of an LB film monolayer with a secondary level of organization in the monolayer imparted by the inter- and intramolecular cross-linking among the carbazole units. This study should provide a basis for monolayer film materials based on combining the LB technique and electrochemical cross-linking for nanostructuring superstructures at the air-water interface.