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PubMed2003

N[bond]C(alpha) bond dissociation energies and kinetics in amide and peptide radicals. Is the dissociation a non-ergodic process?

Dissociations of aminoketyl radicals and cation radicals derived from beta-alanine N-methylamide, N-acetyl-1,2-diaminoethane, N(alpha)-acetyl lysine amide, and N(alpha)-glycyl glycine amide are investigated by combined density functional theory and Møller-Plesset perturbational calculations with the goal of elucidating the mechanism of electron capture dissociation (ECD) of larger peptide and protein ions. The activation energies for dissociations of N[bond]C bonds in aminoketyl radicals decrease in the series N[bond]CH(3) > N-CH(2)CH(2)NH(2) >> N[bond]CH(2)CONH(2) approximately N[bond]CH(CONH(2))(CH(2))(4)NH(2). Transition state theory rate constants for dissociations of N[bond]C(alpha) bonds in aminoketyl radicals and cation-radicals indicate an extremely facile reaction that occurs with unimolecular rate constants >10(5) s(-1) in species thermalized at 298 K in the gas phase. In neutral aminoketyl radicals the N[bond]C(alpha) bond cleavage results in fast dissociation. In contrast, N[bond]C(alpha) bond cleavage in aminoketyl cation-radicals results in isomerization to ion-molecule complexes that are held together by strong hydrogen bonds. The facile N[bond]C(alpha) bond dissociation in thermalized ions indicates that it is unnecessary to invoke the hypothesis of non-ergodic behavior for ECD intermediates.

Alanine↗
PubMed2002

D/H amide isotope effect in model alpha-helical peptides.

The contribution of amide related hydrogen bonds to protein stability has recently been evaluated using the "Cm experiment", which measures the D/H amide isotope effect in proteins. We show here using isolated alpha-helical peptides that there is a significant effect of denaturant concentration on the measured D/H isotope effect, and that valid comparison of different proteins requires correcting for differences in denaturant (GdmHCl) concentration. Finally our results suggest that H-bonds in an isolated alpha-helix may contribute more to helix stability because of less strain compared to those in helical proteins and that the buried helical H-bonds in helical proteins are not necessarily energetically more favorable than solvent exposed H-bonds in isolated helices.

Alanine↗
PubMed2003

Twisted amide reduction under Wolff-Kishner conditions: synthesis of a benzo-1-aza-adamantane derivative.

A synthesis of 4,5-benzo-1-aza-tricyclo[4.3.1.1(3,8)]undecane (1), a benzo-1-aza-adamantane derivative, is described and features a previously unknown application of the Wolff-Kishner reduction of a nonresonance stabilized or "twisted" amide. An intermediate amino ester is converted to a severely "twisted amide", which, when exposed to hydrazine in alcohol, provides the corresponding "twisted" amino hydrazone. Wolff-Kishner conditions (KOH/ethylene glycol, 200 degrees C) provide the reduced target 1 without hydrolysis to amino acid derivatives. These operations are conveniently performed in a single flask in high yield.

Adamantane↗
PubMed2003

The amide rotational barriers in picolinamide and nicotinamide: NMR and ab initio studies.

Pyridine carboxamides are a class of medicinal agents with activity that includes the reduction of iron-induced renal damage, the regulation of nicotinamidase activity, and radio- and chemosensitization. Such pharmacological activities, and the prevalence of the carboxamide moiety and the importance of amide rotations in biology, motivate detailed investigation of energetics in these systems. In this study, we report the use of dynamic nuclear magnetic resonance to measure the amide rotational barriers in the pyridine carboxamides picolinamide and nicotinamide. The activation enthalpies and entropies of DeltaH++ = 12.9 +/- 0.3 kcal/mol and DeltaS++ = -7.7 +/- 0.9 cal/mol K for nicotinamide and DeltaH++ = 18.3 +/- 0.4 kcal/mol and DeltaS++ = +1.3 +/- 1.0 cal/mol K for picolinamide report a substantial energetic difference for these regioisomers. Ab initio calculations of the rotational barriers are in good agreement with the experimentally determined values and help partition the 5.4 kcal/mol enthalpy difference into its major contributions. Of principal importance are the variations in steric interactions in the ground states of picolinamide and nicotinamide, superior pi electron donation from the pyridine ring in the transition state of nicotinamide, and an intramolecular hydrogen bond in the ground state of picolinamide.

Amides↗
PubMed2003

Mechanism of cis-enamide formation from N-(alpha-silyl)allyl amides: synthetic potential of stepwise dyotropic rearrangements.

A novel transformation of silyl amides to N-cis-propenyl amides was recently reported, the reaction of which is a formal 10-electron double sigmatropic, or dyotropic, rearrangement. Density functional calculations (B3LYP/6-311++G(3d,3p)//B3LYP/6-31G(d)) have been carried out to investigate the mechanism of this reaction. A two-step process involving sequential 1,4-silyl and 1,4-hydrogen shifts is predicted. The 1,3-dipolar azomethine ylide intermediate profits from charge stabilization by allylic resonance and phenyl conjugation. The consecutive thermal migration of two sigma-bonds (stepwise dyotropic rearrangement) is an example of a host of reactions with synthetic potential.

Allyl Compounds↗
PubMed2003

Measurements of carbon to amide-proton distances by C-H dipolar recoupling with 15N NMR detection.

A new magic-angle spinning NMR method for measuring internuclear distances between a 13C-labeled site and amide protons is described. The magnetization of the protons evolves under homonuclear decoupling and the recoupled 13C-1H dipolar interaction, which provides simple spin-pair REDOR curves if only one 13C-labeled site is present. The modulation of the amide proton HN is detected via short 1H-15N cross polarization followed by 15N detection. The method is demonstrated on two specifically 13C- and 15N-labeled peptides, with 13C-HN distances from 2.2 to ca. 6 A. This technique promises to be particularly useful for measuring distances between 13C=O and H-15N groups, to identify hydrogen bonds in peptides and proteins.

Amides↗
PubMed2003

Expanding Pd-catalyzed C-N bond-forming processes: the first amidation of aryl sulfonates, aqueous amination, and complementarity with Cu-catalyzed reactions.

The first general method for the Pd-catalyzed amination of aryl tosylates and benzenesulfonates was developed utilizing ligand 1, which belongs to a new generation of biaryl monophosphine ligands. In addition, the new catalyst system for the first time enables amidation of aryl arenesulfonates and aqueous amination protocols that do not necessitate the use of cosolvents. The substrate scope has been significantly expanded to include aryl halides containing primary amides and free carboxylic acid groups. In the case of multifunctional substrates, the Pd-catalyzed amination can provide selectivity that is complementary to the Cu-catalyzed C-N bond-forming processes.

Amides↗
PubMed2003

Palladium-catalyzed alpha-arylation of esters and amides under more neutral conditions.

Two procedures for the alpha-arylation of carbonyl compounds under conditions that are more neutral than those of reactions of aryl halides with alkali metal enolates are reported. The first procedure rests upon the development of catalysts bearing the hindered pentaphenylferrocenyl di-tert-butylphosphine (Q-phos) and the highly reactive dimeric Pd(I) complex {P(t-Bu)3]PdBr}2. By this procedure, zinc enolates prepared from alpha-bromo esters and amides react with aryl halides to form alpha-aryl esters and amides in high yields under mild conditions with 1-2 mol % catalyst and with remarkable functional group tolerance. By the second procedure, silyl ketene and silyl ketimine acetals react with aryl bromides in the presence of substoichiometric zinc fluoride, 1 mol % Pd(dba)2, and 2 mol % P(t-Bu)3 in DMF solvent at 80 degrees C. Reactions of zinc tert-butyl acetate and propionate enolates and trimethylsilyl ketene acetals of tert-butyl propionate and methyl isobutyrate with aryl bromides bearing electron-donating and potentially reactive, base-sensitive electron-withdrawing groups and with pyridyl bromides are reported. In addition, the diastereoselective coupling of phenyl bromide with an imide enolate bearing the Evans auxiliary is reported, and this study shows that racemization of base-sensitive stereocenters does not occur during the coupling process under these more neutral conditions.

Amides↗
PubMed2005

A new spin probe of protein dynamics: nitrogen relaxation in 15N-2H amide groups.

(15)N spin relaxation data have provided a wealth of information on protein dynamics in solution. Standard R(1), R(1)(rho), and NOE experiments aimed at (15)N[(1)H] amide moieties are complemented in this work by HA(CACO)N-type experiments allowing the measurement of nitrogen R(1) and R(1)(rho) rates at deuterated (15)N[(2)D] sites. Difference rates obtained using this approach, R(1)((15)N[(1)H]) - R(1)((15)N[(2)D]) and R(2)((15)N[(1)H]) - R(2)((15)N[(2)D]), depend exclusively on dipolar interactions and are insensitive to (15)N CSA and R(ex) relaxation mechanisms. The methodology has been tested on a sample of peptostreptococcal protein L (63 residues) prepared in 50% H(2)O-50% D(2)O solvent. The results from the new and conventional experiments are found to be consistent, with respect to both local backbone dynamics and overall protein tumbling. Combining several data sets permits evaluation of the spectral density J(omega(D) + omega(N)) for each amide site. This spectral density samples a uniquely low frequency (26 MHz at a 500 MHz field) and, therefore, is expected to be highly useful for characterizing nanosecond time scale local motions. The spectral density mapping demonstrates that, in the case of protein L, J(omega(D) + omega(N)) values are compatible with the Lipari-Szabo interpretation of backbone dynamics based on the conventional (15)N relaxation data.

Amides↗
PubMed2005

Chemical shift anisotropy tensors of carbonyl, nitrogen, and amide proton nuclei in proteins through cross-correlated relaxation in NMR spectroscopy.

The principal components and orientations of the chemical shift anisotropy (CSA) tensors of the carbonyl (C'), nitrogen (N), and amide proton (H(N)) nuclei of 64 distinct amide bonds in human ubiquitin have been determined in isotropic solution by a set of 14 complementary auto- and cross-correlated relaxation rates involving the CSA interactions of the nuclei of interest and several dipole-dipole (DD) interactions. The CSA parameters thus obtained depend to some degree on the models used for local motions. Three cases have been considered: restricted isotropic diffusion, three-dimensional Gaussian axial fluctuations (3D-GAF), and independent out-of-plane motions of the NH(N) vectors with respect to the peptide planes.

Amides↗
PubMed2005

Catalytic ester-amide exchange using group (IV) metal alkoxide-activator complexes.

A process for preparation of amides from unactivated esters and amines has been developed using a catalytic system comprised of group (IV) metal alkoxides in conjunction with additives including 1-hydroxy-7-azabenzotriazole (HOAt). In general, ester-amide exchange proceeds using a variety of structurally diverse esters and amines without azeotropic reflux to remove the alcohol byproduct. Initial mechanistic studies on the Zr(Ot-Bu)4-HOAt system revealed that the active catalyst is a novel, dimeric zirconium complex as determined by X-ray crystallography.

Amides↗
PubMed2006

Hydrogen-bonding-mediated anthranilamide homoduplexes. Increasing stability through preorganization and iterative arrangement of a simple amide binding site.

This paper describes the assembly of two new series of self-complementary duplexes by making use of amide units, the simplest assembling units of hydrogen bonding, as binding sites. All the new monomers possess a rigidified anthranilamide skeleton, which is stabilized by intramolecular hydrogen bonding. Amide units are iteratively introduced to one side of the preorganized skeletons to facilitate the formation of intermolecular hydrogen bonding. Compounds 2 and 3 bear two and three CONH(2) units, respectively, while 4, 6, and 7 are incorporated with two, three, and four AcNH units, respectively. For comparison, compound 5, which is similar to 4 but contains one AcNH and one CF(3)CONH unit, is also prepared. X-ray diffraction analysis of 2, 4, and 5 revealed homodimeric motifs in the solid state which are stabilized by two or more intermolecular hydrogen bonds. (1)H NMR investigations in CDCl(3) indicated that all the compounds form hydrogen-bonded homoduplexes. Duplexes 3.3, 6.6, and 7.7 are highly stable in CDCl(3), with a lower K(assoc) limit of 2.3 x 10(5) M(-1). The K(assoc) values of the three duplexes in more polar CDCl(3)/CD(3)CN (9:1, v/v) were determined with the (1)H NMR dilution method. The result opens the way for the development of new polymeric duplexes of well-ordered structures.

Amides↗
PubMed2006

Effects of lysine acetylation in a beta-hairpin peptide: comparison of an amide-pi and a cation-pi interaction.

The acetylation of lysine is a common posttranslational modification of histone proteins, and the interaction of acetylated lysines with aromatic rings is commonly observed in transcriptionally relevant protein-protein interactions. To determine the nature of this interaction and its potential role in protein structure and function, the effect of lysine acetylation on its interaction with tryptophan has been investigated within the context of a beta-hairpin peptide. Acetylation of Lys results in the replacement of a cation-pi interaction with an amide-pi interaction. Despite the loss of positive charge, the interaction energy is not significantly perturbed, although the geometry of interaction is influenced such that the amide NH interacts directly with the Trp ring. Thermodynamic analysis indicates an enthalpic driving force for the stabilization, indicating a polar-pi interaction. Acyl lysine analogues formyl lysine and trifluoroacetyl lysine were used to further investigate the sterics and electronics of the interaction.

Acetylation↗
PubMed2006

Elucidation of hydrolysis mechanisms for fatty acid amide hydrolase and its Lys142Ala variant via QM/MM simulations.

Fatty acid amide hydrolase (FAAH) is a serine hydrolase that degrades anandamide, an endocannabinoid, and oleamide, a sleep-inducing lipid, and has potential applications as a therapeutic target for neurological disorders. Remarkably, FAAH hydrolyzes amides and esters with similar rates; however, the normal preference for esters reemerges when Lys142 is mutated to alanine. To elucidate the hydrolysis mechanisms and the causes behind this variation of selectivity, mixed quantum and molecular mechanics (QM/MM) calculations were carried out to obtain free-energy profiles for alternative mechanisms for the enzymatic hydrolyses. The methodology features free-energy perturbation calculations in Monte Carlo simulations with PDDG/PM3 as the QM method. For wild-type FAAH, the results support a mechanism, which features proton transfer from Ser217 to Lys142, simultaneous proton transfer from Ser241 to Ser217, and attack of Ser241 on the substrate's carbonyl carbon to yield a tetrahedral intermediate, which subsequently undergoes elimination with simultaneous protonation of the leaving group by a Lys142-Ser217 proton shuttle. For the Lys142Ala mutant, a striking multistep sequence is proposed with simultaneous proton transfer from Ser241 to Ser217, attack of Ser241 on the carbonyl carbon of the substrate, and elimination of the leaving group and its protonation by Ser217. Support comes from the free-energy results, which well reproduce the observation that the Lys142Ala mutation in FAAH decreases the rate of hydrolysis for oleamide significantly more than for methyl oleate.

Alanine↗
PubMed2005

Analysis of Piperaceae germplasm by HPLC and LCMS: a method for isolating and identifying unsaturated amides from Piper spp extracts.

A method for extraction and high performance liquid chromatography-mass spectrometer (HPLC-MS) analysis of the medicinally important genus Piper (Piperaceae) was developed. This allows for a rapid and accurate measure of unsaturated amides, or piperamides, in black pepper, Piper nigrum L., and in wild species from Central America. Reflux extraction provided the highest recovery of piperine (>80%) from leaf and peppercorn material. HPLC analysis using a binary gradient of acetonitrile and water separated the major amide peaks between 5 and 12 min. Atmospheric pressure chemical ionization (APCI)-MS improved the detection limit to 0.2 ng, 10-fold below the 2 ng limit of the HPLC-diode array detector (DAD) based on linear standard curves between 0.1 and 250 microg/mL (R2 = 0.999). The HPLC-MS method identified pellitorine, piperylin, 4,5-dihydropiperlonguminine, piperlonguminine, 4,5-dihydropiperine, piperine, and pipercide. The biological activity of six Costa Rican Piper species assessed by mosquito larval bioassays correlated well with piperamide content.

Aedes↗
PubMed1995

Substituted (1,2-diarylethyl)amide acyl-CoA:cholesterol acyltransferase inhibitors: effect of polar groups on in vitro and in vivo activity.

Substituted (1,2-diarylethyl)amides have been prepared and evaluated for their ability to inhibit microsomal acyl-CoA:cholesterol acyltransferase activity in vitro and to lower hepatic cholesteryl ester content in vivo in a cholesterol-fed hamster. Simple unsubstituted (diarylethyl)amides were potent inhibitors in vitro but showed poor activity in vivo. Introduction of polar groups at specific locations on the diarylethylamine moiety decreased in vitro activity but increased in vivo activity. Both effects were highly structure dependent, suggesting specific interactions which were mediating activity in each model. Optimization of these opposing effects led to compounds which were potent in both models.

Amides↗
PubMed1994

Relationships between structure and kinetics of cyclization of 2-aminoaryl amides: potential prodrugs of cyclization-activated aromatic mustards.

2-Nitroaryl amides of general structure I are proposed as bioreducible prodrugs, capable of releasing cytotoxic aminoaniline mustards V on bioactivation by spontaneous cyclization of the resulting 2-aminoarylamides II via a tetrahedral intermediate, III. This concept allows separate optimization of the substituent effects influencing nitro-group reduction and mustard reactivity. A series of model 2-aminoaryl amides has been synthesized, and their rates of cyclization have been studied; these varied by a factor of more than 50,000-fold (kobs from 0.00040 to 21 min-1) at pH 2.4. For three compounds studied in detail, the rates were linearly dependent of pH, indicating that no change in the mechanism of the rate-determining step occurs over the pH range studied. The nucleophilicity of the amino group had a modest influence on the kinetics of cyclization, with electron-withdrawing groups slowing the rate. The geometry of the compound was also important, with structure-activity relationships indicating that the rate of cyclization is greatly enhanced by the preorganization of the molecule. In contrast, 4-substitution on the leaving aniline by a variety of groups had little effect on the cyclization reaction. These results are consistent with the rate-determining step being formation of the tetrahedral intermediate. These model studies suggest that the phenyldimethylacetamide system could be developed as a prodrug system for the bioreductively-triggered release of amines. Further substantial rate enhancements appear possible by alterations in the geometry of the system, whereas substitution of electron-withdrawing groups (required to raise the nitro-group reduction potential into the appropriate range) has only relatively modest retardation effects on rates of cyclization. More rigid systems may also be useful; a nitronaphthaleneacetamide analogue cyclized spontaneously during nitro-group reduction, suggesting a very short half-life for the reduced intermediate (amine or hydroxylamine).

Amides↗
PubMed1992

Novel inhibitors of prolyl 4-hydroxylase. 2. 5-Amide substituted pyridine-2-carboxylic acids.

A series of 5-[(arylcarbonyl)amino]- and 5-(arylcarbamoyl)pyridine-2-carboxylic acids has been prepared and tested for activity as inhibitors of the enzyme prolyl 4-hydroxylase (EC 1.14.11.2). All the analogues prepared were inhibitors of the enzyme in vitro, the best compounds being equipotent with the known inhibitor pyridine-2,5-dicarboxylic acid (9). Like 9 these amidic analogues were not active in a cultured embryonic chick tendon cell model, considered to be a predictor of in vivo activity. The activity of the amides is not consistent with the model described for the mode of action of 9 with the enzyme and aspects of this are discussed.

Amides↗