Functional Mimics of Glutathione Peroxidase: Bioinspired Synthetic Antioxidants

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the biological system's ability to detoxify these reactive intermediates. Mammalian cells have elaborate antioxidant defense mechanisms to control the damaging effects of ROS. Glutathione peroxidase (GPx), a selenoenzyme, plays a key role in protecting the organism from oxidative damage by catalyzing the reduction of harmful hydroperoxides with thiol a ``catalytic triad'' with tryptophan and glutamine, which cofactors. The selenocysteine residue at the active site forms activates the selenium moiety for an efficient reduction of peroxides. After the discovery that ebselen, a synthetic organoselenium compound, mimics the catalytic activity of GPx both in vitro and in vivo, several research groups developed a number of small-molecule selenium compounds as functional mimics of GPx, either by modifying the basic structure of ebselen or by incorporating some structural features of the native enzyme. The synthetic mimics reported in the literature can be classified in three major categories: (i) cyclic selenenyl amides having a Se-N bond, (ii) diaryl diselenides, and (iii) aromatic or aliphatic monoselenides. Recent studies show that ebselen exhibits very poor GPx activity when aryl or benzylic thiols such as PhSH or BnSH are used as cosubstrates. Because the catalytic activity of each GPx mimic largely depends on the thiol cosubstrates used, the difference in the thiols causes the discrepancies observed in different studies. In this Account, we demonstrate the effect of amide and amine substituents on the GPx activity of various organoselenium compounds. The existence of strong Se ... O/N interactions in the selenenyl sulfide intermediates significantly reduces the GPx activity. These interactions facilitate an attack of thiol at selenium rather than at sulfur, leading to thiol exchange reactions that hamper the formation of catalytically active selenol. Therefore, any substituent capable of enhancing the nucleophilic attack of thiol at sulfur in the selenenyl sulfide state would enhance the antioxidant potency of organoselenium compounds. Interestingly, replacement of the sec-amide substituent by a tert-amide group leads to a weakening of Se ... 0 interactions in the selenenyl sulfide intermediates. This modification results in 10- to 20-fold enhancements in the catalytic activities. Another strategy involving the replacement of tert-amide moieties by tert-amino substituents further increases the activity by 3- to 4-fold. The most effective modification so far in benzylamine-based GPx mimics appears to be either the replacement of a tert-amino substituent by a sec-amino group or the introduction of an additional 6-methoxy group in the phenyl ring. These strategies can contribute to a remarkable enhancement in the GPx activity. In addition to enhancing catalytic activity, a change in the substituents near the selenium moiety alters the catalytic mechanisms. The mechanistic investigations of functional mimics are useful not only for understanding the complex chemistry at the active site of GPx but also for designing and synthesizing novel antioxidants and anti-inflammatory agents.

Addition of amines and halogens to fullerenes C60 and C70

In solution phase, aliphatic amines add on to fullerenes; vapourization of graphite in presence of methylamine gives nitrogeneous C60 derivatives. Reactions of C60 with SbCl5 and liquid Br2 yield halogen adducts.

A Thermodynamic Proposal for the Exposition of Critically and other Subtle Features in Self-Deflagrating Ammonium Perchlorate Systems

A first comprehensive investigation on the deflagration of ammonium perchlorate (AP) in the subcritical regime, below the low pressure deflagration limit (LPL, 2.03 MPa) christened as regime I$^{\prime}$, is discussed by using an elegant thermodynamic approach. In this regime, deflagration was effected by augmenting the initial temperature (T$_{0}$) of the AP strand and by adding fuels like aliphatic dicarboxylic acids or polymers like carboxy terminated polybutadiene (CTPB). From this thermodynamic model, considering the dependence of burning rate ($\dot{r}$) on pressure (P) and T$_{0}$, the true condensed (E$_{\text{s,c}}$) and gas phase (E$_{\text{s,g}}$) activation energies, just below and above the surface respectively, have been obtained and the data clearly distinguishes the deflagration mechanisms in regime I$^{\prime}$ and I (2.03-6.08 MPa). Substantial reduction in the E$_{\text{s,c}}$ of regime I$^{\prime}$, compared to that of regime I, is attributed to HClO$_{4}$ catalysed decomposition of AP. HClO$_{4}$ formation, which occurs only in regime I$^{\prime}$, promotes dent formation on the surface as revealed by the reflectance photomicrographs, in contrast to the smooth surface in regime I. The HClO$_{4}$ vapours, in regime I$^{\prime}$, also catalyse the gas phase reactions and thus bring down the E$_{\text{s,g}}$ too. The excess heat transferred on to the surface from the gas phase is used to melt AP and hence E$_{\text{s,c}}$, in regime I, corresponds to the melt AP decomposition. It is consistent with the similar variation observed for both the melt layer thickness and $\dot{r}$ as a function of P. Thermochemical calculations of the surface heat release support the thermodynamic model and reveal that the AP sublimation reduces the required critical exothermicity of 1108.8 kJ kg$^{-1}$ at the surface. It accounts for the AP not sustaining combustion in the subcritical regime I$^{\prime}$. Further support for the model comes from the temperature-time profiles of the combustion train of AP. The gas and condensed phase enthalpies, derived from the profile, give excellent agreement with those computed thermochemically. The $\sigma _{\text{p}}$ expressions derived from this model establish the mechanistic distinction of regime I$^{\prime}$ and I and thus lend support to the thermodynamic model. On comparing the deflagration of strand against powder AP, the proposed thermodynamic model correctly predicts that the total enthalpy of the condensed and gas phases remains unaltered. However, 16% of AP particles undergo buoyant lifting into the gas phase in the `free board region' (FBR) and this renders the demarcation of the true surface difficult. It is found that T$_{\text{s}}$ lies in the FBR and due to this, in regime I$^{\prime}$, the E$_{\text{s,c}}$ of powder AP matches with the E$_{\text{s,g}}$ of the pellet. The model was extended to AP/dicarboxylic acids and AP/CTPB mixture. The condensed ($\Delta $H$_{1}$) and gas phase ($\Delta $H$_{2}$) enthalpies were obtained from the temperature profile analyses which fit well with those computed thermochemically. The $\Delta $H$_{1}$ of the AP/succinic acid mixture was found just at the threshold of sustaining combustion. Indeed the lower homologue malonic acid, as predicted, does not sustain combustion. In vaporizable fuels like sebacic acid the E$_{\text{s,c}}$ in regime I$^{\prime}$, understandably, conforms to the AP decomposition. However, the E$_{\text{s,c}}$ in AP/CTPB system corresponds to the softening of the polymer which covers AP particles to promote extensive condensed phase reactions. The proposed thermodynamic model also satisfactorily explains certain unique features like intermittent, plateau and flameless combustion in AP/ polymeric fuel systems.

Nitrogen Derivatives Of C-60 And C-70 - Interaction Of Fullerenes With Nitrogen In Gas-Phase

Mass spectrometric studies show that contact-arc vaporization of graphite in a partial atmosphere of N2 or NH3 yields nitrogenous products tentatively assigned to species such as C70N2, C59N6, C59N4 and C59N2 involving addition of or substitution by nitrogen along with the species due to C2 and C4 losses. Mass spectrometry and other techniques have been employed to identify products of the nucleophilic addition of aliphatic amines to C60 and C70 in solution phase.

Synthesis and Antioxidant Activity of Peptide-Based Ebselen Analogues

A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by H-1, C-13, and Se-77 NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H2O2, tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a co-substrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO2Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO2Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration.

Production of biosurfactant “Biosur-Pm” by Pseudomonas maltophila CSV89: characterization and role in hydrocarbon uptake

Pseudomonas maltophilia CSV89, a soil bacterium, produces an extracellular biosurfactant, ''Biosur-Pm''. The partially purified product is nondialyzable and chemically composed of 50% protein and 12-15% sugar, which indicates the complex nature of Biosur-Pm. It reduces the surface tension of water from 73 to 53 x 10(-3) N m(-1) and has a critical micellar concentration of 80 mg/l. Compared to aliphatic hydrocarbons, Biosur-Pm shows good activity against aromatic hydrocarbons. The emulsion formed is stable and does not require any metal ions for emulsification. The kinetics of Biosur-Pm production suggest that its synthesis isa growth-associated and pH-dependent process. At pH 7.0, cells produced more Biosur-Pm with less cell surface hydrophobicity. At pH 8.0, however, the cells produced less Biosur-Pm with more cell surface hydrophobicity and showed a twofold higher affinity for aromatic hydrocarbons compared to the cells grown at pH 7.0. The Biosur-Pm showed a pH-dependent release, stimulated growth of the producer strain on mineral salts medium with 1-naphthoic acid when added externally, and facilitated the conversion of salicylate to catechol. All these results suggest that Biosur-Pm is probably a cell-wall component and helps in hydrocarbon assimilation/uptake.

Coordination self-assembly of tetranuclear Pt(II) macrocycles with an organometallic backbone for sensing of acyclic dicarboxylic acids

Coordination self-assembly of a series of tetranuclear Pt(II) macrocycles containing an organometallic backbone incorporating ethynyl functionality is presented. The 1 : 1 combination of a linear acceptor 1,4-bistrans-Pt(PEt3)(2)(NO3)(ethynyl)]benzene (1) with three different dipyridyl donor `clips' (L-a-L-c) afforded three 2 + 2] self-assembled Pt-4(II) macrocycles (2a-2c) in quantitative yields, respectively L-a = 1,3-bis-(3-pyridyl)isothalamide; L-b = 1,3-bis(3-pyridyl)ethynylbenzene; L-c = 1,8-bis(4-pyridyl)ethynylanthracene]. These macrocycles were characterized by multinuclear NMR (H-1 and P-31); ESI-MS spectroscopy and the molecular structures of 2a and 2b were established by single crystal X-ray diffraction analysis. These macrocycles (2a-2c) are fluorescent in nature. The amide functionalized macrocycle 2a is used as a receptor to check the binding affinity of aliphatic acyclic dicarboxylic acids. Such binding affinity is examined using fluorescence and UV-Vis spectroscopic methods. A solution state fluorescence study showed that macrocycle 2a selectively binds (K-SV = 1.4 x 10(4) M-1) maleic acid by subsequent enhancement in emission intensity. Other aliphatic dicarboxylic acids such as fumaric, succinic, adipic, mesaconic and itaconic acids caused no change in the emission spectra; thereby demonstrating its potential use as a macrocyclic receptor in distinction of maleic acid from other aliphatic dicarboxylic acids.

Photophysical behavior of poly(propyl ether imine) dendrimer in the presence of nitroaromatic compounds

This paper deals with a study of the photophysical property of poly(ether imine) (PETIM) dendritic macromolecule in the presence of aromatic compounds. The inherent photoluminescence property of the dendrimer undergoes quenching in the presence of guest aromatic nitro-compounds. From life-time measurements study, it is inferred that the lifetimes of luminescent species of the dendrimer are not affected with nitrophenols as guest molecules, whereas nitrobenzenes show a marginal change in the lifetimes of the species. Raman spectral characteristic of the macromolecular host-guest complex is conducted in order to identify conformational change of the dendrimer and a significant change in the stretching frequencies of methylene moieties of the dendrimer is observed for the complex with 1,3,5-trinitrobenzene, when compared to other complexes, free host and guest molecules. The photophysical behavior of electron-rich, aliphatic, neutral dendritic macromolecule in the presence of electron-deficient aromatic molecules is illustrated in the present study. (C) 2012 Elsevier B.V. All rights reserved.

Single-step synthesis of internally functionalizable hyperbranched polyethers

Radical catalyzed thiol-ene reaction has become a useful alternative to the Huisgen-type azide-yne click reaction as it helps expand the variability in reaction conditions as well as the range of clickable entities. In this study, the direct generation of a hyperbranched polyether (HBPE) having decyl units at the periphery and a pendant allyl group on every repeat unit of the polymer backbone is described; the allyl groups serve as a reactive handle for postpolymerization modifications and permits the generation of a variety of internally functionalized HBPEs. In this design, the AB(2) monomer carries two decylbenzyl ether units (B-functionality), an aliphatic OH (A-functionality) and a pendant allyl group within the spacer segment; polymerization of the monomer readily occurs at 150 degrees C via melt transetherification process by continuous removal of 1-decanol under reduced pressure. The resulting HBPE has a hydrophobic periphery due to the presence of numerous decyl chains, while the allyl groups that remain unaffected during the melt polymerization provides an opportunity to install a variety of functional groups within the interior; thiol-ene click reaction with two different thiols, namely 3-mercaptopropionic acid and mercaptosuccinic acid, generated interesting amphiphilic structures. Preliminary field emission scanning electron microscope (FESEM) and Atomic Force Microscopy (AFM) imaging studies reveal the formation of fairly uniform spherical aggregates in water with sizes ranging from 200 to 400 nm; this suggests that these amphiphilic HBPs is able to reconfigure to generate jellyfish-like conformations that subsequently aggregate in an alkaline medium. The internal allyl functional groups were also used to generate intramolecularly core-crosslinked HBPEs, by the use of dithiol crosslinkers; gel permeation chromatography traces provided clear evidence for reduction in the size after crosslinking. In summary, we have developed a simple route to prepare core-clickable HBPEs and have demonstrated the quantitative reaction of the allyl groups present within the interior of the polymers; such HB polymeric systems that carry numerous functional groups within the core could have interesting applications in analyte sequestration and possibly sensing, especially from organic media. (c) 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4125-4135

Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt

Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H center dot center dot center dot O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.

Amine-functionalized multiwall carbon nanotubes impart osteoinductive and bactericidal properties in poly(epsilon-caprolactone) composites

Poly(epsilon-caprolactone) (PCL) is an aliphatic polyester widely used for biomedical applications but lacks the mechanical properties desired for many load-bearing orthopedic applications. The objective of this study was to prepare and characterize PCL composites incorporating multiwall carbon nanotubes (MWNTs) with different surface functional groups. PCL composites were prepared by melt-mixing with three different types of MWNTs: pristine (pMWNT), amine functionalized (aMWNT), and carboxyl functionalized (cMWNT). Melt rheology and scanning electron microscopy indicated good dispersion of the nanotubes in the matrix. Tensile strength and elastic modulus of the polymer was significantly increased by the incorporation of MWNTs and further enhanced by favorable interactions between PCL and aMWNTs. Thermal analysis revealed that MWNTs act as heterogeneous nucleation sites for crystallization of PCL and increase polymer crystallinity. Incorporation of functionalized MWNTs increased the surface water wettability of PCL. Osteoblast proliferation and differentiation was significantly enhanced on functionalized composites. aMWNT composites also exhibited the best bactericidal response. This study demonstrates that surface functionalization of MWNTs profoundly influences the properties of PCL and amine-functionalization offers the optimal combination of mechanical properties, osteogenesis and antimicrobial response. These results have important implications for designing nanocomposites for use in orthopedics.

RES-TOCSY: A facile approach for accurate determination of magnitudes, and relative signs of (n)J(HF)

The RES-TOCSY experiment for accurate determination of heteronuclear (n)J(HF) is reported. The main feature of the proposed technique is the accurate measurement of magnitudes of heteronuclear couplings from the displacement of cross sections of the 2D spectrum and their relative signs from the slopes of their displacement vectors. The experiment is highly advantageous as the couplings of smaller magnitudes hidden within line widths could also be accurately determined, and also in situations when the spectrum does not display any coupling fine structures. The efficient utility of the developed pulse sequence is unambiguously established on fluorine containing aromatic and aliphatic molecules. (C) 2014 Elsevier B.V. All rights reserved.

Allosteric Transition Induced by Mg2+ Ion in a Transactivator Monitored by SERS

We demonstrate the utility of the surface-enhanced Raman spectroscopy (SERS) to monitor conformational transitions in protein upon ligand binding. The changes in protein's secondary and tertiary structures were monitored using amide and aliphatic/aromatic side chain vibrations. Changes in these bands are suggestive of the stabilization of the secondary and tertiary structure of transcription activator protein C in the presence of Mg2+ ion, whereas the spectral fingerprint remained unaltered in the case of a mutant protein, defective in Mg2+ binding. The importance of the acidic residues in Mg2+ binding, which triggers an overall allosteric transition in the protein, is visualized in the molecular model. The present study thus opens up avenues toward the application of SERS as a potential tool for gaining structural insights into the changes occurring during conformational transitions in proteins.

CHLORAL HYDRATE AS A WATER CARRIER FOR THE EFFICIENT DEPROTECTION OF ACETALS, DITHIOACETALS, AND TETRAHYDROPYRANYL ETHERS IN ORGANIC SOLVENTS

The efficient deprotection of several acetals, dithioacetals, and tetrahydropyranyl (THP) ethers under ambient conditions, using chloral hydrate in hexane, is described. Excellent yields were realized for a wide range of both aliphatic and aromatic substrates. The method is characterized by mild conditions (room temperatures or below), simple workup, and the ready availability of chloral hydrate. High chemoselectivity was also observed in the deprotection, acetonides, esters, and amides being unaffected under the reaction conditions. Products were generally purified chromatographically and identified spectrally. These results constitute a novel addition to current methodology involving a widely employed deprotection tactic in organic synthesis. It seems likely that the mechanism of the reaction involves adsorption of the substrate on the surface of the sparingly soluble chloral hydrate.

SELECTIVE ALDEHYDE REDUCTION IN KETOALDEHYDES WITH NaBH4-Na2CO3-H2O AT ROOM TEMPERATURES

A variety of aliphatic and aromatic ketoaldehydes were reduced to the corresponding ketoalcohols with a mixture of sodium borohydride (1.2 equivalents) and sodium carbonate (sixfold molar excess) in water. Reactions were performed at room temperatures over (typically) 2 h, and yields of isolated products generally ranged from 70% to 85%. A biscarbonate-borane complex, (BH3)(2)CO2](2-) 2Na(+), possibly formed from the reagent mixture, is likely the active reductant. The moderated reactivity of this acylborane species would explain the chemoselectivity observed in the reactions. The readily available reagents and the mild aqueous conditions make for ease of operation and environmental compatibility, and make a useful addition to available methodology.