Amide-Based Glutathione Peroxidase Mimics: Effect of Secondary and Tertiary Amide Substituents on Antioxidant Activity

A series of secondary and tertiary amide-substituted diselenides were synthesized and studied for their GPx-like antioxidant activities using H2O2 Cum-OOH, and tBuOOH as substrates and PhSH as thiol co-substrate.The effect of substitution at the free -NH group of the amide moiety in the sec-amide-based diselenides on GPx activity was analyzed by detailed experimental and theoretical methods. It is observed that substitution at the free -NH group significantly enhances the GPx-like activities of the sec-amide-based diselenides, mainly by reducing the Se center dot center dot center dot O nonbonded interactions. The reduction in strength of the Se center dot center dot center dot O interaction upon introduction of N,N-dialkyl substituents not only prevents the undesired thiol exchange reactions, but also reduces the stability of selenenyl sulfide intermediates. This leads to a facile disproportionation of the selenenyl sulfide to the corresponding diselenide, which enhances the catalytic activity. The mechanistic investigations indicate that the reactivity of diselenides having sec-or tert-amide moieties with PhSH is extremely slow; indicating that the first step of the catalytic cycle involves the reaction between the diselenides and peroxide to produce the corresponding selenenic and seleninic acids.

Amide-based Room Temperature Molten Salt as Solvent cum Stabilizer for Metallic Nanochains

A simple and efficient method for spontaneous organization of long assemblies of gold nanoparticles is described. This is achieved in a molten solvent containing acetamide, urea and ammonium nitrate that acts as a solvent cum stabilizer. There is no external aggregating agent or stabilizing agent added to the system. Depending on the concentration of the metal salt in the ternary melt, either chain-like assemblies or individual nanoparticles could be obtained. The amine groups present in the components of the melt (acetamide and urea) help in the stabilization of nanoparticles. Ammonium ions present in the eutectic mixture are likely to assist in the organization of the particles. The method is simple, highly reproducible and does not require any templating agent for the formation of chain-like assemblies.

Amide-catalysed isomerisation of 5,6-dihydroisoquinolines: a novel synthesis of 1,2-dihydroisoquinolines

Knoevenagel condensation of 2-acylcyclohexanones or 2-ethoxycarbonylcyclohexanone with either cyanoacetamide or malononitrile followed by silver salt alkylation gave the 5,6,7,8-tetrahydroisoquinolines (3a–i). Chromic acid oxidation of the 5,6,7,8-tetrahydroisoquinolines (3a–i) to the corresponding tetralones (4a–i) followed by sodium borohydride reduction and p-toluenesulphonic acid-catalysed dehydration of the resulting alcohols (5a–i) gave the 5,6-dihydroisoquinolines (6a–i). Reaction of 5,6-dihydroisoquinolines (6a–g) with potassium amide in liquid ammonia gave a mixture of the 1,3-dihydroisoquinolines (7a–g) and the isoquinolines (8a–g). The C-1 unsubstituted 1,2-dihydroisoquinoline (7c) was found to be very unstable. In the case of the 5,6-dihydroisoquinolines (6h and 6i), reaction of potassium amide in liquid ammonia resulted in a mixture of 1-aminoisoquinoline (9) and the isoquinolines (8h and 8i). All the above compounds have been characterised by spectral data. A probable pathway for the formation of the 1,2-dihydroisoquinolines (7a–g) and the isoquinolines (8a–i) is suggested.

Amide catalysed facile isomerization of 5,6-dihydroisoquinolines: synthesis of stable 1,2-dihydroisoquinolines

Stable 1,2-dihydroisoquinolines have been synthesized by an amide catalysed novel isomerization reaction of 5,6-dihydroisoquinolines.

Amide-catalysed isomerisation of 5,6-dihydroisoquinolines: a novel synthesis of 1,2-dihydroisoquinolines

Knoevenagel condensation of 2-acylcyclohexanones or 2-ethoxycarbonylcyclohexanone with either cyanoacetamide or malononitrile followed by silver salt alkylation gave the 5,6,7,8-tetrahydroisoquinolines (3a–i). Chromic acid oxidation of the 5,6,7,8-tetrahydroisoquinolines (3a–i) to the corresponding tetralones (4a–i) followed by sodium borohydride reduction and p-toluenesulphonic acid-catalysed dehydration of the resulting alcohols (5a–i) gave the 5,6-dihydroisoquinolines (6a–i). Reaction of 5,6-dihydroisoquinolines (6a–g) with potassium amide in liquid ammonia gave a mixture of the 1,3-dihydroisoquinolines (7a–g) and the isoquinolines (8a–g). The C-1 unsubstituted 1,2-dihydroisoquinoline (7c) was found to be very unstable. In the case of the 5,6-dihydroisoquinolines (6h and 6i), reaction of potassium amide in liquid ammonia resulted in a mixture of 1-aminoisoquinoline (9) and the isoquinolines (8h and 8i). All the above compounds have been characterised by spectral data. A probable pathway for the formation of the 1,2-dihydroisoquinolines (7a–g) and the isoquinolines (8a–i) is suggested.

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.

Probing acid-amide intermolecular hydrogen bonding by NMR spectroscopy and DFT calculations

Benzene carboxylic acids and Benzamide act as their self-complement in molecular recognition to form inter-molecular hydrogen bonded dimers between amide and carboxylic acid groups, which have been investigated by H-1, C-13 and N-15 NMR spectroscopy. Extensive NMR studies using diffusion ordered spectroscopy (DOSY), variable temperature 1D, 2D NMR, established the formation of heterodimers of benzamide with benzoic acid, salicylic acid and phenyl acetic acid in deuterated chloroform solution. Association constants for the complex formation in the solution state have been determined. The results are ascertained by X-ray diffraction in the solid state. Intermolecular interactions in solution and in solid state were found to be similar. The structural parameters obtained by X-ray diffraction studies are compared with those obtained by DFT calculations. (C) 2012 Elsevier B.V. All rights reserved.

Crystal-structure analysis of cis-X-pro-containing peptidomimetics: understanding the steric interactions at cis X-pro amide bonds

Catch the twist: The cis Piv-Pro conformer (Piv=pivaloyl) of peptides is no longer inaccessible. Any cis X-Pro tertiary-amide-bond conformer can be stabilized in crystals of peptides by accommodating the unavoidable distortion of the dihedral angle of the peptide bond to the carbonyl group of the Pro residue (see picture), in this case through ni−1→πi* interactions. Steric clashes were not observed in the cis Piv-Pro rotamers studied.

Redox regulation of protein tyrosine phosphatase 1B (PTP1B): Importance of steric and electronic effects on the unusual cyclization of the sulfenic acid intermediate to a sulfenyl amide

The redox regulation of protein tyrosine phosphatase 1B (PTP1B) via the unusual transformation of its sulfenic acid (PTP1B-SOH) to a cyclic sulfenyl amide intermediate is studied by using small molecule chemical models. These studies suggest that the sulfenic acids derived from the H2O2-mediated reactions o-amido thiophenols do not efficiently cyclize to sulfenyl amides and the sulfenic acids produced in situ can be trapped by using methyl iodide. Theoretical calculations suggest that the most stable conformer of such sulfenic acids are stabilized by n(O) -> sigma* (S-OH) orbital interactions, which force the -OH group to adopt a position trans to the S center dot center dot center dot O interaction, leading to an almost linear arrangement of the O center dot center dot center dot S-O moiety and this may be the reason for the slow cyclization of such sulfenic acids to their corresponding sulfenyl amides. On the other hand, additional substituents at the 6-position of o-amido phenylsulfenic acids that can induce steric environment and alter the electronic properties around the sulfenic acid moiety by S center dot center dot center dot N or S center dot center dot center dot O nonbonded interactions destabilize the sulfenic acids by inducing strain in the molecule. This may lead to efficient the cyclization of such sulfenic acids. This model study suggests that the amino acid residues in the close proximity of the sulfenic acid moiety in PTP1B may play an important role in the cyclization of PTP1B-SOH to produce the corresponding sulfenyl amide.

The Modified Selenenyl Amide, M-hydroxy Ebselen, Attenuates Diabetic Nephropathy and Diabetes-Associated Atherosclerosis in ApoE/GPx1 Double Knockout Mice

Seleno-organic glutathione peroxidase (GPx) mimetics, including ebselen (Eb), have been tested in in vitro studies for their ability to scavenge reactive oxygen and nitrogen species, including hydrogen peroxide and peroxynitrite. In this study, we investigated the efficacies of two Eb analogues, m-hydroxy ebselen (ME) and ethanol-ebselen (EtE) and compared these with Eb in cell based assays. We found that ME is superior in attenuating the activation of hydrogen peroxide-induced pro-inflammatory mediators, ERK and P38 in human aortic endothelial cells. Consequently, we investigated the effects of ME in an in vivo model of diabetes, the ApoE/GPx1 double knockout (dKO) mouse. We found that ME attenuates plaque formation in the aorta and lesion deposition within the aortic sinus of diabetic dKO mice. Oxidative stress as assessed by 8-OHdG in urine and nitrotyrosine immunostaining in the aortic sinus and kidney tubules, was reduced by ME in diabetic dKO mice. ME also attenuated diabetes-associated renal injury which included tubulointerstitial fibrosis and glomerulosclerosis. Furthermore, the bioactivity of the pro-fibrotic cytokine transforming growth factor-beta (TGF-beta) as assessed by phospho-Smad2/3 immunostaining was attenuated after treatment with ME. TGF-beta-stimulated increases in collagen I and IV gene expression and protein levels were attenuated by ME in rat kidney tubular cells. However, in contrast to the superior activity of ME in in vitro and cell based assays, ME did not further augment the attenuation of diabetes-associated atherosclerosis and renal injury in our in vivo model when compared with Eb. In conclusion, this study strengthens the notion that bolstering GPx-like activity using synthetic mimetics may be a useful therapeutic strategy in lessening the burden of diabetic complications. However, these studies highlight the importance of in vivo analyses to test the efficacies of novel Eb analogues, as in vitro and cell based assays are only partly predictive of the in vivo situation.

Steric and Electronic Interactions Controlling the cis/trans Isomer Equilibrium at X-Pro Tertiary Amide Motifs in Solution

A systematic understanding of the noncovalent interactions that influence the structures of the cis conformers and the equilibrium between the cis and the trans conformers, of the X-Pro tertiary amide motifs, is presented based on analyses of H-1-, C-13-NMR and FTIR absorption spectra of two sets of homologous peptides, X-Pro-Aib-OMe and X-Pro-NH-Me (where X is acetyl, propionyl, isobutyryl and pivaloyl), in solvents of varying polarities. First, this work shows that the cis conformers of any X-Pro tertiary amide motif, including Piv-Pro, are accessible in the new motifs X-Pro-Aib-OMe, in solution. These conformers are uniquely observable by FTIR spectroscopy at ambient temperatures and by NMR spectroscopy from temperatures as high as 273 K. This is made possible by the persistent presence of n(i-1i)* interactions at Aib, which also influence the disappearance of steric effects at these cis X-Pro rotamers. Second, contrary to conventional understanding, the energy contribution of steric effects to the cis/trans equilibrium at the X-Pro motifs is found to be nonvariant (0.54 +/- 0.02 kcal/mol) with increase in steric bulk on the X group. Third, the current studies provide direct evidence for the weak intramolecular interactions namely the n(i-1i)*, the N-Pro center dot center dot center dot Hi+1 (C(5)a), and the C-7 hydrogen bond that operate and influence the structures, stabilities, and dynamics between different conformational states of X-Pro tertiary amide motifs. NMR and IR spectral data suggest that the cis conformers of X-Pro motifs are ensembles of short-lived rotamers about the C-X-N-Pro bond. (c) 2013 Wiley Periodicals, Inc. Biopolymers 101: 66-77, 2014.

Amide Functionalized Microporous Organic Polymer (Am-MOP) for Selective CO2 Sorption and Catalysis

We report the design and synthesis of an amide functionalized microporous organic polymer (Am-MOP) prepared from trimesic acid and p-phenylenediamine using thionyl chloride as a reagent. Polar amide (CONH) functional groups act as a linking unit between the node and spacer and constitute the pore wall of the continuous polymeric network. The strong covalent bonds between the building blocks (trimesic acid and p-phenylenediamine) through amide bond linkages provide high thermal and chemical stability to Am-MOP. The presence of a highly polar pore surface allows selective CO2 uptake at 195 K over other gases such as N-2, Ar, and O-2. The CO2 molecule interacts with amide functional groups via Lewis acid base type interactions as demonstrated through DFT calculations. Furthermore, for the first time Am-MOP with basic functional groups has been exploited for the Knoevenagel condensation reaction between aldehydes and active methylene compounds. Availability of a large number of catalytic sites per volume and confined microporosity gives enhanced catalytic efficiency and high selectivity for small substrate molecules.

Mechanochemical Synthesis of Amide Functionalized Porous Organic Polymers

Two porous organic polymers decorated with the amide functionality were synthesized mechanochemically and their properties were compared with the ones prepared by conventional solution mediated method. All the POPs were subjected to gas and water vapor sorption studies. The mechanochemically synthesized POPs have less surface area and show moderate adsorption properties compared to the solution mediated POPs. The amide based POPs show remarkable stability in water and concentrated acids.

3 `-Amino-5 `-carboxymethy1-3 `,5 `-dideoxy nucleosides for the synthesis of fully amide-linked RNA mimics

A convenient protocol is developed for the synthesis of 3 `-N-(fluorenylmethoxycarbonyl)-amino]-5 `-carboxymethyl derivatives of all four natural ribonucleosides from cheap chiral pool compound glucose. Synthesis of fully amide-linked RNA analogues of small oligonucleotides containing, for the first time, all four nucleoside amino acids using standard solid phase Fmoc-chemistry is described. (C) 2014 Elsevier Ltd. All rights reserved.