Synthesis and esterolytic chemistry of some (dialkylamino) pyridine-functionalized micellar aggregates. Evidence of catalytic turnover

Four new (dialkylamino)pyridine-functionalized surfactants have been synthesized. Micelles were generated either from the surfactant alone in aqueous buffer (pH 8.5 or 9.0) or by comicellization in 1 x 10(-3)-1 x 10(-4) M aqueous micellar cetyltrimethylammonium bromide (CTABr) solution at pH 8.5 or 9.0. Such aggregates were used to cleave p-nitrophenyl alkanoates or p-nitrophenyl diphenylphosphate. The nucleophilic reagents and the second-order ''catalytic'' rate constants toward esterolysis of the substrate p-nitrophenyl octanoate (at 25 degrees C, pH 9.0) were [cat.] = 1 x 10(-4) M, [CTABr] = 1 x 10(-3) M, and k(cat.) = 440.13 M(-1) s(-1) for 1b, [cat.] = 5 x 10(-4) M, [CTABr] = 5 x 10(-4) M, and k(cat.) = 30.8 M(-1) s(-1) for 1c, [cat.] = 5 x 10(-4) M, [CTABr] = 5 x 10(-3) M, and k(cat.) = 183.64 M(-1) s(-1) for 2a, and [cat.] = 3 x 10(-4) M and k(cat.) = 54.1 M(-1) s(-1) for 2b. The catalytic systems, especially 1b/CTABr and 2a/CTABr, also conferred significantly greater reactivity toward the esters derived from alkanoic acids of moderate chain length (C-6-C-10) during hydrolytic cleavages relative to their shorter and longer counterparts. Importantly, the catalytic systems comprising the coaggregates of either neutral 1b and CTABr (1:10) or anionic 2a and CTABr (1:10) conformed to the Michaelis-Menten kinetic scheme and demonstrated turnover behavior in the presence of excess substrate.

Intramolecular Reactivity - Keto Participation in the Hydrolysis of N-Methyl-N-(9-Oxobicyclo[3.3.1]Nonan-2-Alpha-YL) Morpholinium Iodide, and A Cannizzaro-Type Reaction of 3-(2-Oxocyclohexyl)Propanal

Mechanistic studies of two intramolecular processes, nucleophilic displacement of N-methylmorpholinium in N-methyl-N-{9-oxobicyclo[3,3,1]nonan-2 alpha-yl}morpholinium iodide, anchimerically assisted by keto carbonyl, and a Cannizzaro-type reaction of 3-(2-oxocyclohexyl)propanal, occurring via axial hydride transfer onto the cyclohexanone, are reported.

Deiodination of Thyroid Hormones by Iodothyronine Deiodinase Mimics: Does an Increase in the Reactivity Alter the Regioselectivity?

Organoselenium compounds as functional mimics of iodothyronine deiodinase are described. The naphthyl-based compounds having two selenol groups are remarkably efficient in the inner-ring deiodination of thyroxine. The introduction of a basic amino group in close proximity to one of the selenol moieties enhances the deiodination. This study suggests that an increase in the nucleophilic reactivity of the conserved Cys residue at the active site of deiodinases is very important for effective deiodination.

Accessing the disallowed conformations of peptides employing amide-to-imidate modification

Selective modification of the C-terminal amide in peptides to dihydrooxazine (a novel stable imidate isostere) by intramolecular nucleophilic cyclo-O-alkylation of the corresponding N-(3-bromopropyl)amides results in constraining of the C-terminal residue in natively disallowed conformations both in crystals and in solution.

Conformational Basis for Substrate Recruitment in Protein Tyrosine Phosphatase 10D

The coordinated activity of protein tyrosine phosphatases (PTPs) is crucial for the initiation, modulation, and termination of diverse cellular processes. The catalytic activity of this protein depends on a nucleophilic cysteine at the active site that mediates the hydrolysis of the incoming phosphotyrosine substrate. While the role of conserved residues in the catalytic mechanism of PTPs has been extensively examined, the diversity in the mechanisms of substrate recognition and modulation of catalytic activity suggests that other, less conserved sequence and structural features could contribute to this process. Here we describe the crystal structures of Drosophila melanogaster PTP10D in the apo form as well as in a complex with a substrate peptide and an inhibitor. These studies reveal the role of aromatic ring stacking interactions at the boundary of the active site of PTPs in mediating substrate recruitment. We note that phenylalanine 76, of the so-called KNRY loop, is crucial for orienting the phosphotyrosine residue toward the nucleophilic cysteine. Mutation of phenylalanine 76 to leucine results in a 60-fold decrease in the catalytic efficiency of the enzyme. Fluorescence measurements with a competitive inhibitor, p-nitrocatechol sulfate, suggest that Phe76 also influences the formation of the enzyme-substrate intermediate. The structural and biochemical data for PTP10D thus highlight the role of relatively less conserved residues in PTP domains in both substrate recruitment and modulation of reaction kinetics.

Deoxythiosugar Derivatives with Furano, Pyrano, and Septano Motifs from L-Gulono-1,4-lactone and D-Glycero-D-gulo-heptono-1,4-lactone

A short synthesis of thiosugar derivatives mimicking furanose, pyranose, and septanose structures has been achieved starting from L-gulono-1,4-lactone and D-glucoheptono-1,4-lactone. Different strategies used in the synthesis are: (1) a nucleophilic displacement and Michael addition; (2) epoxide ring opening and Michael addition; (3) epoxide ring opening and nucleophilic displacement process; and (4) double nucleophilic displacement. All of these reactions used benzyltriethylammonium tetrathiomolybdate, (BnEt3N)(2)MoS4 as the sulfur-transfer reagent.

Inhibition of Lactoperoxidase-Catalyzed Oxidation by Imidazole-Based Thiones and Selones: A Mechanistic Study

Herein, we describe the synthesis and biomimetic activity of a series of N,N-disubstituted thiones and selones that contain an imidazole pharmacophore. The N,N-disubstituted thiones do not show any inhibitory activity towards LPO-catalyzed oxidation reactions, but their corresponding N,N-disubstituted selones exhibit inhibitory activity towards LPO-catalyzed oxidation reactions. Substituents on the N atom of the imidazole ring appear to have a significant effect on the inhibition of LPO-catalyzed oxidation and iodination reactions. Selones 16, 17, and 19, which contain methyl, ethyl, and benzyl substituents, exhibit similar inhibition activities towards LPO-catalyzed oxidation reactions with IC50 values of 24.4, 22.5, and 22.5M, respectively. However, their activities are almost three-fold lower than that of the commonly used anti-thyroid drug methimazole (MMI). In contrast, selone 21, which contains a NCH2CH2OH substituent, exhibits high inhibitory activity, with an IC50 value of 7.2M, which is similar to that of MMI. The inhibitory activity of these selones towards LPO-catalyzed oxidation/iodination reactions is due to their ability to decrease the concentrations of the co-substrates (H2O2 and I2), either by catalytically reducing H2O2 (anti-oxidant activity) or by forming stable charge-transfer complexes with oxidized iodide species. The inhibition of LPO-catalyzed oxidation/iodination reactions by N,N-disubstituted selones can be reversed by increasing the concentration of H2O2. Interestingly, all of the N,N-disubstituted selones exhibit high anti-oxidant activities and their glutathione peroxidase (GPx)-like activity is 4-12-fold higher than that of the well-known GPx-mimic ebselen. These experimental and theoretical studies suggest that the selones exist as zwitterions, in which the imidazole ring contains a positive charge and the selenium atom carries a large negative charge. Therefore, the selenium moieties of these selones possess highly nucleophilic character. The 77SeNMR chemical shifts for the selones show large upfield shift, thus confirming the zwitterionic structure in solution.

De novo synthesis of 1-deoxythiosugars

A short and efficient chemical synthesis of biologically potent and novel 1-deoxythiosugars is accomplished. Introduction of sulfur mediated by benzyltriethylammonium tetrathiomolybdate, as a sulfur transfer reagent through nucleophilic double displacement of tosylate in alpha,omega-di-O-tosyl aldonolactones in an intramolecular fashion is the key feature. The subsequent reduction of thiosugar lactones with borohydride exchange resin (BER) offers a number of deoxythiosugars in good overall yield. (C) 2013 Elsevier Ltd. All rights reserved.

Remarkable influence of secondary catalyst site on enantioselective desymmetrization of cyclopentenedione

An efficient, robust and highly enantioselective catalytic desymmetrization of 2,2-disubstituted cyclopentene-1,3-diones is developed via direct vinylogous nucleophilic addition of deconjugated butenolides. A remarkable influence of the secondary catalyst site on the enantioselectivity points towards an intriguing mechanistic scenario, possibly by triggering a change in catalyst conformation.

Catalytic asymmetric desymmetrization approaches to enantioenriched cyclopentanes

Catalytic asymmetric desymmetrization represents an excellent strategy for accessing highly functionalized chiral building blocks. However, the application of desymmetrization for the synthesis of enantio-enriched cyclopentane derivatives remained limited, when compared to chiral cyclohexanes. We have recently developed a desymmetrization protocol for prochiral 2,2-disubstituted cyclopentene-1,3-diones by direct catalytic asymmetric vinylogous nucleophilic addition of deconjugated butenolides. In this perspective, we give an overview of asymmetric desymmetrization reactions leading to enantioenriched cyclopentanes and their derivatives. The focus is kept confined to the diverse nature of reactions used for this purpose. A brief discussion on the potential future directions is also provided.

AN EXPEDITIOUS COUMARIN SYNTHESIS VIA A ``PSEUDOCYCLOADDITION'' BETWEEN SALICYLALDEHYDES AND KETENE

A variety of salicylaldehydes effected tandem nucleophilic addition onto ketene, leading to corresponding coumarins in good yields under mild conditions. This pseudocycloaddition represents a very mild variant of the historic Perkin synthesis of coumarin (which remains of key interest in both perfumery and several emerging areas).

Engineering nanostructured polymer blends with controlled nanoparticle location for excellent microwave absorption: a compartmentalized approach

In order to obtain better materials, control over the precise location of nanoparticles is indispensable. It is shown here that ordered arrangements of nanoparticles, possessing different characteristics (electrical/ magnetic dipoles), in the blend structure can result in excellent microwave absorption. This is manifested from a high reflection loss of ca. -67 dB for the best blend structure designed here. To attenuate electromagnetic radiation, the key parameters of high electrical conductivity and large dielectric/magnetic loss are targeted here by including a conductive material multiwall carbon nanotubes, MWNTs], ferroelectric nanostructured material with associated relaxations in the GHz frequency barium titanate, BT] and lossy ferromagnetic nanoparticles nickel ferrite, NF]. In this study, bi-continuous structures were designed using 50/50 (by wt) blends of polycarbonate (PC) and polyvinylidene fluoride (PVDF). The MWNTs were modified using an electron acceptor molecule, a derivative of perylenediimide, which facilitates p-p stacking with the nanotubes and stimulates efficient charge transport in the blends. The nanoscopic materials have specific affinity towards the PVDF phase. Hence, by introducing surface-active groups, an ordered arrangement can be tailored. To accomplish this, both BT and NF were first hydroxylated followed by the introduction of amine-terminal groups on the surface. The latter facilitated nucleophilic substitution reactions with PC and resulted in their precise location. In this study, we have shown for the first time that by a compartmentalized approach, superior EM attenuation can be achieved. For instance, when the nanoparticles were localized exclusively in the PVDF phase or in both the phases, the minimum reflection losses were ca. -18 dB (for the MWNT/BT mixture) and -29 dB (for the MWNT/NF mixture), and the shielding occurred primarily through reflection. Interestingly, by adopting the compartmentalized approach wherein the lossy materials were in the PC phase and the conductive materials (MWNT) were in the PVDF phase, outstanding reflection losses of ca. -57 dB (for the BT and MWNT combination) and -67 dB (for the NF and MWNT combination) were noted and the shielding occurred primarily through absorption. Thus, the approach demonstrates that nanoscopic structuring in the blends can be achieved under macroscopic processing conditions and this strategy can further be explored to design microwave absorbers.

Introduction of a catalytic triad increases the glutathione peroxidase-like activity of diaryl diselenides

Reactive oxygen species (ROS)-mediated diseased states are of major concern in modern day life. Under oxidative stress conditions, the cellular antioxidants deplete, leading to several biological disorders. Small molecule mimics of different antioxidant enzymes are found to be useful in supplementing the biological systems to detoxify ROS. In this study, we have synthesized a series of amine or amide-based diselenides containing an additional amino group as glutathione peroxidase (GPx) mimetics. These diselenides act as a catalytic triad model of the native GPx featuring two basic amino groups near the selenium centre. A comparison of the catalytic activities reveals that the additional amino group increases the activity significantly in the presence of aromatic thiols. Deprotonation of thiol by an additional amine either stabilizes the selenolate intermediate or facilitates the nucleophilic attack of thiol in other intermediates. The Se-77 NMR experiments and DFT calculations show that the amino group does not have any significant effect on the catalytic intermediates. Although the amino moiety increases the nucleophilicity of the thiol, it does not prevent the thiol exchange reactions that take place in the selenenyl sulfide intermediates.

Ru (II)-Catalyzed C-H Activation: Ketone-Directed Novel 1,4-Addition of Ortho C-H Bond to Maleimides

A 1,4-addition with the nucleophilic center generated at the ortho carbon atom of an aromatic ketone in the presence of the highly reactive alpha-C-H bond, using a directing group strategy, is presented. The reaction yields pharmaceutically useful 3-arylated succinimide derivatives. In order to gain understanding of this redox neutral reaction, despite the presence of copper acetate, and to substantiate the lack of Heck-type products, DFT calculations have been carried out.

Tailor-Made Distribution of Nanoparticles in Blend Structure toward Outstanding Electromagnetic Interference Shielding

Engineering blend structure with tailor-made distribution of nanoparticles is the prime requisite to obtain materials with extraordinary properties. Herein, a unique strategy of distributing nanoparticles in different phases of a blend structure has resulted in >99% blocking of incoming electromagnetic (EM) radiation. This is accomplished by designing a ternary polymer blend structure using polycarbonate (PC), poly(vinylidene fluoride) (PVDF), and poly(methyl methacrylate) (PMMA) to simultaneously improve the structural, electrical, and electromagnetic interference shielding (EMI). The blend structure was made conducting by preferentially localizing the multi-wall nanotubes (MWNTs) in the PVDF phase. By taking advantage of pp stacking MWNTs was noncovalently modified with an imidazolium based ionic liquid (IL). Interestingly, the enhanced dispersion of IL-MWNTs in PVDF improved the electrical conductivity of the blends significantly. While one key requisite to attenuate EM radiation (i.e., electrical conductivity) was achieved using MWNTs, the magnetic properties of the blend structure was tuned by introducing barium ferrite (BaFe) nanoparticles, which can interact with the incoming EM radiation. By suitably modifying the surface of BaFe nanoparticles, we can tailor their localization under the macroscopic processing condition. The precise localization of BaFe nanoparticles in the PC phase, due to nucleophilic substitution reaction, and the MWNTs in the PVDF phase not only improved the conductivity but also facilitated in absorption of the incoming microwave radiation due to synergetic effect from MWNT and BaFe. The shielding effectiveness (SE) was measured in X and K-u band, and an enhanced SE of -37 dB was noted at 18 GHz frequency. PMMA, which acted as an interfacial modifier in PC/PVDF blends further, resulting in a significant enhancement in the mechanical properties besides retaining high SE. This study opens a new avenue in designing mechanically strong microwave absorbers with a suitable combination of materials.