Showing papers on "Amide published in 1998"
TL;DR: The UV Raman method appears to be complementary, and in some cases superior, to the existing methods, such as CD, VCD, and absorption spectroscopy, and it will be possible to examine proteins in micelles and other scattering media.
Abstract: We have directly determined the amide band resonance Raman spectra of the “average” pure α-helix, β-sheet, and unordered secondary structures by exciting within the amide π→π* transitions at 206.5 nm. The Raman spectra are dominated by the amide bands of the peptide backbone. We have empirically determined the average pure α-helix, β-sheet, and unordered resonance Raman spectra from the amide resonance Raman spectra of 13 proteins with well-known X-ray crystal structures. We demonstrate that we can simultaneously utilize the amide I, II, and III bands and the Cα−H amide bending vibrations of these average secondary structure spectra to directly determine protein secondary structure. The UV Raman method appears to be complementary, and in some cases superior, to the existing methods, such as CD, VCD, and absorption spectroscopy. In addition, the spectra are immune to the light-scattering artifacts that plague CD, VCD, and IR absorption measurements. Thus, it will be possible to examine proteins in micelles...
286 citations
TL;DR: This work describes here a novel Backbone Amide Linker (BAL) approach, whereby the growing peptide is anchored through a backbone nitrogen, thus allowing considerable flexibility in management of the termini.
Abstract: Peptide targets for synthesis are often desired with C-terminal end groups other than the more usual acid and amide functionalities. Relatively few routes exist for synthesis of C-terminal-modified peptidesincluding cyclic peptidesby either solution or solid-phase methods, and known routes are often limited in terms of ease and generality. We describe here a novel Backbone Amide Linker (BAL) approach, whereby the growing peptide is anchored through a backbone nitrogen, thus allowing considerable flexibility in management of the termini. Initial efforts on BAL have adapted the chemistry of the tris(alkoxy)benzylamide system exploited previously with PAL anchors. Aldehyde precursors to PAL, e.g. 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid, were reductively coupled to the α-amine of the prospective C-terminal amino acid, which was blocked as a tert-butyl, allyl, or methyl ester, or to the appropriately protected C-terminal-modified amino acid derivative. These reductive aminations were carried out either i...
260 citations
TL;DR: A palladium-catalyzed α-arylation of amides was reported in this article, where the palladium catalyst was formed in situ from Pd(dba)2 (dba = trans,trans-dibenzylidene acetone).
Abstract: 2A palladium-catalyzed α-arylation of amides is reported. Intermolecular arylation of N,N-dimethylamides and lactams occurs using aryl halides, silylamide base, and a palladium catalyst. Intramolecular arylation of N-(2-halophenyl)amides occurs using alkoxide base and a palladium catalyst. The palladium catalyst was formed in situ from Pd(dba)2 (dba = trans,trans-dibenzylidene acetone) and BINAP (2,2‘-bis(diphenylphosphino)-1,1‘-binaphthalene). Although the intermolecular arylation of amides is less general than that reported previously for ketones, unfunctionalized and electron-rich aryl halides gave α-arylamides in 48−75% yield and N-methyl-α-phenylpyrrolidinone in 49% yield. These reactions provided the highest yields yet reported for regioselective amide arylations. Intramolecular amide arylation of 2-bromoanilides gave oxindoles in 52−82% yield. Mono- and disubstituted acetanilides gave 1,3-di- and 1,3,3-trisubstituted oxindoles. The use of dioxane, rather than THF, solvent was important for some of ...
258 citations
TL;DR: This chapter provides an overview of this recent progress made on the characterization of amidotransferase structure and mechanism.
Abstract: Amide nitrogen from glutamine is a major source of nitrogen atoms incorporated biosynthetically into other amino acids, purine and pyrimidine bases, amino-sugars, and coenzymes. A family comprised of at least sixteen amidotransferases are known to catalyze amide nitrogen transfer from glutamine to their acceptor substrates. Recent fine structural advances, largely as a result of X-ray crystallography, now provide structure-based mechanisms that help to explain fundamental aspects of the catalytic and regulatory interactions of several of these aminotransferases. This chapter provides an overview of this recent progress made on the characterization of amidotransferase structure and mechanism.
231 citations
TL;DR: A means to alkylate R-imino esters enantioselectively in up to 98% ee and in high chemical yields with enol silanes using chiral catalytic late transition metal phosphine complexes selected from Ag(I), Cu(I, Ni(II), and Pd(II) (eq 2).
Abstract: Over the past several years, highly effective methods for enantioselective aldol additions catalyzed by Lewis acids have been developed.1 Analogous alkylations of imines, however, have not been nearly as well studied nor as successful.2 R-Imino esters are almost unstudied in Lewis acid-catalyzed reactions,3 but are especially attractive imine substrates for the efficient syntheses of natural product precursors,4 pharmaceutically active compounds,5 and nonnatural amino acids;6 the last category has recently received much attention as peptidomimetics7 and in sitedirected mutagenesis studies.8 In a recent report, we demonstrated that select late transition metals can catalyze the cis-trans isomerization of prolyl peptides through simultaneous coordination of the metal to the amide nitrogen (Na) and the side chain carbonyl group (Figure 1, a).9 Catalysis fails to occur on simple amides that do not contain an additional binding site. These results prompted us to investigate whether analogous coordination of a transition metal to the nitrogen of a functionalized imine and a chelating carbonyl group could activate the substrate toward a highly enantioselective addition of nucleophiles (Figure 1, b). From our point of view, activated R-imino esters 1 seemed ideal substrates for Lewis acid catalyzed asymmetric alkylations for several reasons: (1) alkylation occurs readily at the imine carbon with a variety of nucleophiles, (2) the electron-withdrawing R-ester group provides additional activation of the imino group to nucleophilic attack, (3) the imine N and carbonyl O can form a stable five-membered chelate ring with a chiral Lewis acid catalyst (eq 1),10 providing additional rigidity to an activated complex and potentially enhanced product selectivity, and (4) alkylation of imine derivatives 1 with enol silane nucleophiles can lead to substituted γ-oxo R-amino acids (aspartic acid analogues) that comprise a class of interesting and useful biologically active natural compounds.11 We report herein a means to alkylate R-imino esters enantioselectively in up to 98% ee and in high chemical yields with enol silanes using chiral catalytic late transition metal phosphine complexes selected from Ag(I), Cu(I), Ni(II), and Pd(II) (eq 2).
206 citations
TL;DR: Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) was used to determine amide proton/deuteron (H/D) exchange rates, and H/D exchange rates were determined for some 40 peptides covering 65% of the protein sequence.
Abstract: Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) was used to determine amide proton/deuteron (H/D) exchange rates. The method has broad application to the study of protein conformation and folding and to the study of protein-ligand interactions and requires no modifications of the instrument. Amide protons were allowed to exchange with deuterons in buffered D2O at room temperature, pD 7.25. Exchanged deuterons were "frozen" in the exchanged state by quenching at pH 2.5, 0 degree C and analyzed by MALDI-TOF MS. The matrix mixture consisted of 5 mg/mL alpha-cyano-4-hydroxycinnamic acid, acetonitrile, ethanol, and 0.1% TFA. The matrix was adjusted to pH 2.5, and the chilled MALDI target was rapidly dried. Deuteration of amide protons on cyclic AMP-dependent protein kinase was measured after short times of incubation in deuterium by pepsin protein digestion and MALDI-TOF MS analysis. The unseparated peptic digest was analyzed in a single spectrum of the mixture. From five spectra, H/D exchange rates were determined for some 40 peptides covering 65% of the protein sequence.
194 citations
TL;DR: The data support a model in which urea denatures proteins by decreasing the hydrophobic effect and by directly binding to the amide units via hydrogen bonds, and indicate that the enthalpy of amide hydrogen bond formation in water is considerably higher than previously estimated.
Abstract: The effects of urea on protein stability have been studied using a model system in which we have determined the energetics of dissolution of a homologous series of cyclic dipeptides into aqueous urea solutions of varying concentration at 25 degrees C using calorimetry. The data support a model in which urea denatures proteins by decreasing the hydrophobic effect and by directly binding to the amide units via hydrogen bonds. The data indicate also that the enthalpy of amide hydrogen bond formation in water is considerably higher than previously estimated. Previous estimates included the contribution of hydrophobic transfer of the alpha-carbon resulting in an overestimate of the binding between urea and the amide unit of the backbone and an underestimate of the binding enthalpy.
192 citations
TL;DR: In this paper, the dimeric alkaline earth metal bis[bis(trialkylsilyl)phosphanides] were given as the minimum structures according to ab initio calculations for calcium and strontium for gaseous [M(PH2)2]2, whereas for barium the structure of the type M(μ-PH 2)4Ba has to be considered.
158 citations
TL;DR: In this paper, a resorcinarene-based cavitands 2a−e that fold into a deep (8 × 10 A dimensions) open-ended cavity by means of intramolecular hydrogen bonds has been synthesized.
Abstract: A novel class of resorcinarene-based cavitands 2a−e that fold into a deep (8 × 10 A dimensions) open-ended cavity by means of intramolecular hydrogen bonds has been synthesized. As follows from the FTIR and 1H NMR spectral data in apolar solvent, a seam of eight intramolecular hydrogen bonds is stitched along the upper rim of the structure 2a−e; the amide CO...H−N interactions bridge adjacent ringsinterannular bindingand are held in place by the seven-membered intraannular hydrogen bonds. The self-folding in 2a−e is reversibly controlled by solvent and temperature. Complexation of self-folding cavitands 2a−e with organic molecules such as (1-substituted) adamantanes, lactams, and cyclohexane derivatives was demonstrated by 1H NMR spectroscopy in CDCl3, benzene-d6 and p-xylene-d10; the binding energy -ΔG° values of 2−4 kcal mol-1 in p-xylene-d10 at 295 K were calculated. The exchange between complexed and free guest species is slow on the NMR time-scale, and it is proposed that hydrogen bonds are responsib...
158 citations
TL;DR: Using 1H NMR techniques, peptide bonds adjacent to the aromatic amino acid were found to generate a cis isomer population ranging from 0.1% to 1% in dependence on the chain length and the ionization state of the peptide.
Abstract: We present results on the identification and molecular characterization of conformers with secondary cis amide peptide bonds for a number of oligopeptides containing tyrosine and phenylalanine in a...
147 citations
TL;DR: The title amide 1 behaves more like a ketone-up to a point!
Abstract: The title amide 1 behaves more like a ketone-up to a point! The crystal structure of this (90°) twisted amide shows a pyramidal nitrogen atom next to a planar carbonyl group.
TL;DR: The X-ray crystal structure of a catalytic-site mutant EQ208 [Glu208-->Gln] of alpha-amylase from Bacillus subtilis cocrystallized with maltopentaose (G5) and acarbose has been determined by multiple isomorphous replacement at 2.5 A resolution, suggesting that Glu208 acts as ageneral acid and Asp176 as a general base.
TL;DR: It is demonstrated that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide and the insulinotropic action in vitro and in vivo was not impaired significantly by this modification.
Abstract: Glucagon-like peptide-1 (GLP-1) is the most potent endogenous insulin-stimulating hormone. In the present study the plasma stability and biological activity of a GLP-1 analog, [Ser]GLP-1(7-36)amide, in which the second N-terminal amino acid alanine was replaced by serine, was evaluated in vitro and in vivo. Incubation of GLP-1 with human or rat plasma resulted in degradation of native GLP-1(7-36)amide to GLP-1(9-36)amide, while [Ser]GLP-1(7-36)amide was not significantly degraded by plasma enzymes. Using glucose-responsive HIT-T15 cells, [Ser]GLP-1(7-36)amide showed strong insulinotropic activity, which was inhibited by the specific GLP-1 receptor antagonist exendin-4(9-39)amide. Simultaneous i.v. injection of [Ser]GLP-1(7-36)amide and glucose in rats induced a twofold higher increase in plasma insulin levels than unmodified GLP-1(7-36)amide with glucose and a fivefold higher increase than glucose alone. [Ser]GLP-1(7-36)amide induced a 1.5-fold higher increase in plasma insulin than GLP-1(7-36)amide when given 1 h before i.v. application of glucose. The insulinotropic effect of [Ser]GLP-1(7-36)amide was suppressed by i.v. application of exendin-4(9-39)amide. The present data demonstrate that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide. The insulinotropic action in vitro and in vivo was not impaired significantly by this modification.
TL;DR: An exhaustive survey of crystal structure data on simple amides and metal complexes containing monodentate amide ligands has been performed in this article, where structural features are reported as a function of the degree of alkylation of the amide functional group and the type of binding to the metal ion.
TL;DR: In this article, the authors proposed a new reagent CF3H/Base/DMF for trifluoromethyl aryl alcohols, ketones or sulfides.
TL;DR: A series of aliphatic poly(ester amide)s derived from 1,6-hexanediol, glycine, and diacids with a variable number of methylenes (from 2 to 8) have been synthesized and characterized.
Abstract: A series of aliphatic poly(ester amide)s derived from 1,6-hexanediol, glycine, and diacids with a variable number of methylenes (from 2 to 8) have been synthesized and characterized. Infrared spectroscopy shows that the studied polymers present a unique kind of hydrogen bond that is established between their amide groups. Thermal properties as melting, glass transition, and decomposition temperatures are reported. The data indicate that all the polymers are highly crystalline. Thus, different kinds of spherulites (positive and/or negative) were obtained depending on the preparation conditions and on the polymer samples. Moreover, all the polymers crystallized from dilute diol solutions as ribbonlike crystals where a regular folding habit and a single hydrogen bond direction could be deduced. A test of enzymatic hydrolysis was employed to assess the potential biodegradability of these polymers. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 1271–1282, 1998
TL;DR: The intramolecular hydroamination of certain allenes, bearing amine or sulfonyl amide groups at the terminus of the carbon chain, proceeded smoothly in the presence of catalytic amounts of palladium complex ([( η 3 -C 3 H 5 )PdCl] 2 -dppf) under weakly acidic conditions (0.15-1.0 equivalent of acetic acid).
TL;DR: Histatin 5, unlike other naturally occurring antimicrobial polypeptides such as magainins, defensins, and tachyplesins, does not adopt amphiphilic structure, precluding its insertion into microbial membranes and formation of ion channels across membranes.
Abstract: The solution structure of human salivary histatin 5 (D-S-H-A-K-R-H-H-G-Y-K-R-K-F-H-E-K-H-H-S-H-R-G-Y) was examined in water (pH 3.8) and dimethyl sulfoxide solutions using 500 MHz homo- and heteronuclear two-dimensional (2D) nmr. The resonance assignment of peptide backbone and side-chain protons was accomplished by 2D total correlated spectroscopy and nuclear Overhauser effect (NOE) spectroscopy. The high JNH-C alpha H values (> or = 7.4 Hz), absence of any characteristic NH-NH (i, i + 1) or C alpha H-C beta H (i, i + 3) NOE connectivities, high d delta/dT values (> or = 0.004 ppm K-1) and the fast 1H/2H amide exchange suggest that histatin 5 molecules remain unstructured in aqueous solution at pH 3.8. In contrast, histatin 5 prefers largely alpha-helical conformation in dimethyl sulfoxide solution as evident from the JNH-C alpha H values ( 1) intramolecular backbone amide hydrogen bonds in polar aprotic medium such as dimethyl sulfoxide. The interside-chain hydrogen bonding and salt-bridge type interactions that normally stabilize the helical structure of linear peptides in aqueous solutions are not observed. Histatin 5, unlike other naturally occurring antimicrobial polypeptides such as magainins, defensins, and tachyplesins, does not adopt amphiphilic structure, precluding its insertion into microbial membranes and formation of ion channels across membranes. Electrostatic (ionic type) and hydrogen bonding interactions of the positively charged and polar residues with the head groups of microbial membranes or with a membrane-bound receptor could be the initial step involved in the mechanism of antimicrobial activity of histatins.
TL;DR: The result of repetitive biodegradability analyses for poly-aspartic acid suggested the complete biodegradation is possible and the type of amide linkage affected the calcium ion chelating ability.
Abstract: Various types of poly(aspartic acid)s, which were poly(α-l-aspartic acid), poly(α-d-aspartic acid), poly(β-l-aspartic acid), and poly(α,β-d,l-aspartic acid)s, were prepared, and their biodegradabilities using the OECD 301C method and calcium ion chelating abilities were measured to clarify the relationship between the structure of poly(aspartic acid)s and these properties. Distinct tendencies were found both between the number of amide protons and biodegradability and between the ratio of the dicarboxylic acid end groups to the dicarboxylic acid end group plus succinimide end group and biodegradability. The chirality of the aspartic acid unit and the type of amide linkage in poly(aspartic acid) had no apparent effect on the biodegradability of poly(aspartic acid). The result of repetitive biodegradability analyses for poly-aspartic acid suggested the complete biodegradation is possible. Regarding the calcium ion chelating ability, only the type of amide linkage affected the calcium ion chelating ability. ...
TL;DR: The ligand nicotinamide (L) is used to propagate the linear coordination geometry of AgL2 into 1-D and 2-D assemblies via a combination of coordinate covalent bonds and specific intermolecular hydrogen-bond interactions.
TL;DR: A series of dimeric through octameric (1→5) amide-linked sialooligomers were prepared using solid-phase peptide methods on Rink resin with Fmoc protecting group chemistry to create oligomers suitable for high-performance liquid chromatography.
Abstract: A series of dimeric through octameric (1→5) amide-linked sialooligomers were prepared using solid-phase peptide methods on Rink resin with Fmoc protecting group chemistry. The oligomers were conjug...
TL;DR: The reaction of 1 equiv of (Et2O)LiC6H3-2,6-Trip2 (Trip = C6H2-2-4,6i-Pr3) with either GeCl2−dioxane or SnI2 in ether affords the synthetically useful monomeric aryl−metal halides Ge(Cl){C 6H 3-2.6-6-...
TL;DR: EPR spin trapping together with UV-VIS spectroscopy has been employed to examine the reaction of HOCl with amino acids and some small peptides in the presence of free amine groups on both amino acid side chains and at the N-terminus as discussed by the authors.
Abstract: EPR spin trapping together with UV–VIS spectroscopy has been employed to examine the reaction of HOCl with amino acids and some small peptides. Evidence has been obtained for the formation and subsequent decomposition of short-lived chloramine derivatives from free amine groups present on both amino acid side-chains and at the N-terminus. Radical formation, detected by EPR spin trapping, occurs concurrently with chloramine decomposition. This process is enhanced by, but does not require, the presence of added Fe2+. With some substrates nitrogen-centred (aminyl, RNH˙ or RNH2˙+) radicals, formed from cleavage of the N–Cl bond of the chloramine, can be detected. These initial aminyl radicals undergo a variety of hydrogen atom abstraction, rearrangement and fragmentation reactions to give carbon-centred species. Evidence has been obtained for both inter- and intra-molecular (1,2- and 1,5-) hydrogen atom abstraction reactions, decarboxylation and β-scission processes. The last of these only occurs to a significant extent where the resulting radical is highly stabilised, for example, by aromatic substituents, and results in loss of the amino acid side-chain. Studies with N-acetyl derivatives and peptides are consistent with reaction of HOCl at amide (peptide) bonds to give transient chloramides which rapidly decompose to give (undetected) amidyl [˙N(R)C(O)R′] radicals. These species undergo rapid 1,2-hydrogen atom shift reactions to give (stabilised) α-carbon radicals with most peptides. Evidence has also been obtained for the occurrence of hydrogen atom abstraction and decarboxylation reactions with these substrates.
TL;DR: Novel conformation-dependent Raman bands in a native alpha-helix assembly are identified, amide I and amide III assignments proposed previously for filamentous viruses are confirmed, and new Raman assignments for the packaged ssDNA are facilitated.
Abstract: The filamentous virus fd consists of a single-stranded DNA genome sheathed by 2700 copies of a 50-residue α-helical subunit (protein pVIII) and serves as a model assembly of α-helices. To advance vibrational assignments for the α-helix, we have investigated Raman spectra of fd virions containing 13C and 2H (deuterium) labels at various main-chain sites of the pVIII subunits. 13C was introduced at specific peptide carbonyls, while deuterium was introduced at selected α-carbon (Cα) and amide nitrogen positions. Interpretation of the Raman spectra reveals a previously unrecognized α-helix band in the spectral interval 730−745 cm-1, tentatively assigned to a carbonyl in-plane bending mode (amide IV). Experimental evidence has also been obtained for a distinctive α-helix marker near 1345 cm-1, assigned to a coupled Cα−H bending and Cα−C stretching mode. The fd virions containing 13C-labeled carbonyls exhibit unexpectedly complex amide I profiles, consisting of multiple band components. Amide I splitting result...
TL;DR: In this article, a short chain ferrocenylalkyl disulfides and nonelectroactive unsubstituted alkanethiols were synthesized and self-assembled on vapor-deposited gold.
Abstract: Short chain ferrocenylalkyl disulfides, where n < 9, with the amide functionality (−OCN) at variable positions were synthesized and self-assembled on vapor-deposited gold. The effects of interchain hydrogen bonding on the stability, packing density, electron transfer rate and the formal potential of these self-assembled monolayers were investigated using cyclic voltammetry and infrared reflection−absorption spectroscopy. Interchain hydrogen bonding appeared to enhance the stability of these monolayers, although the packing densities were lower than that expected for a full monolayer. The electrochemical behavior of coadsorbed monolayers of ferrocenylalkyl disulfides and nonelectroactive unsubstituted alkanethiols was also examined. In these coadsorbed systems, an unexpected negative shift in the formal potential of the ferrocenyl compounds with the amide linkages was observed. This was attributed to disorder arising from the disruption of the hydrogen bonds within the monolayer caused by the alkanethiol “...
TL;DR: It is shown that the secondary structure prediction accuracy of proteins by multivariate data analysis methods increases slightly, if the side chain absorbances of the residues asparagine, glutamine, aspartic acid, glutamic acid, arginine, tyrosine, and lysine are subtracted from the amide I and amide II region.
TL;DR: The purified amidase was shown to bel-enantioselective towards α-hydroxy- and α-aminoamides and the highest affinities of the acyl-enzyme complexes for hydroxylamine were obtained with short, polar or unsaturated amides as acyl donors.
Abstract: The enantioselective amidase from Rhodococcus sp. strain R312 was produced in Escherichia coli and was purified in one chromatographic step. This enzyme was shown to catalyze the acyl transfer reaction to hydroxylamine from a wide range of amides. The optimum working pH values were 7 with neutral amides and 8 with alpha-aminoamides. The reaction occurred according to a Ping Pong Bi Bi mechanism. The kinetic constants demonstrated that the presence of a hydrophobic moiety in the carbon side chain considerably decreased the Km(amide) values (e.g., Km(amide) = 0.1 mM for butyramide, isobutyramide, valeramide, pivalamide, hexanoamide, and benzamide). Moreover, very high turnover numbers (kcat) were obtained with linear aliphatic amides (e.g., kcat = 333 s-1 with hexanoamide), whereas branched-side-chain-, aromatic cycle- or heterocycle-containing amides were sterically hindered. Carboxylic acids, alpha-amino acids, and methyl esters were not acyl donors or were very bad acyl donors. Only amides and hydroxamic acids, both of which contained amide bonds, were determined to be efficient acyl donors. On the other hand, the highest affinities of the acyl-enzyme complexes for hydroxylamine were obtained with short, polar or unsaturated amides as acyl donors (e.g., KmNH2OH = 20, 25, and 5 mM for acetyl-, alanyl-, and acryloyl-enzyme complexes, respectively). No acyl acceptors except water and hydroxylamine were found. Finally, the purified amidase was shown to be L-enantioselective towards alpha-hydroxy- and alpha-aminoamides.
TL;DR: X-ray crystal structures of four HIV-1 RT-carboxanilide complexes reported here reveal that all four inhibitors bind in the usual NNI site, forming binary 1:1 complexes with RT in the absence of substrates with the amide/thioamide bond in cis conformations.
Abstract: The carboxanilides are nonnucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT), of potential clinical importance. The compounds differ in potency and in their retention of potency in the face of drug resistance mutations. Whereas UC-84, the prototype compound, only weakly inhibits many RTs bearing single point resistance mutations, inhibition by UC-781 is little affected. It has been proposed that UC-38 and UC-781 may form quaternary complexes with RT at a site other than the known binding pocket of other NNIs. X-ray crystal structures of four HIV-1 RT-carboxanilide complexes (UC-10, UC-38, UC-84, and UC-781) reported here reveal that all four inhibitors bind in the usual NNI site, forming binary 1:1 complexes with RT in the absence of substrates with the amide/thioamide bond in cis conformations. For all four complexes the anilide rings of the inhibitors overlap aromatic rings of many other NNIs bound to RT. In contrast, the second rings of UC-10, UC-84, and UC-781 do not bind in equivalent positions to those of other "two-ring" NNIs such as alpha-APA or HEPT derivatives. The binding modes most closely resemble that of the structurally dissimilar NNI, Cl-TIBO, with a common hydrogen bond between each carboxanilide NH- group and the main-chain carbonyl oxygen of Lys101. The binding modes differ slightly between the UC-10/UC-781 and UC-38/UC-84 pairs of compounds, apparently related to the shorter isopropylmethanoyl substituents of the anilide rings of UC-38/UC-84, which draws these rings closer to residues Tyr181 and Tyr188. This in turn explains the differences in the effect of mutated residues on the binding of these compounds.
TL;DR: In this paper, a site-specific alkylation procedure for peptide amide functions is described, illustrated with an N-ethyl scan of Leu-enkephalin.
TL;DR: The first systematic investigation of solvent effects on ∆G‡ for hindered C-N bond rotation in carbamates is reported and that this process occurs with a negative ∆S’ for acyclic tertiarycarbamates in aqueous solution.
Abstract: In the 40 years since the inception of dynamic NMR methods, much effort has been invested to quantify and understand the barrier to rotation about the C-N bond in amides.1 Carbamates, which also exhibit the approximately planar N-CdO framework responsible for hindered rotation in amides, have received considerably less attention, although they are important biologically as anticonvulsants, local anesthetics, sedatives, muscle relaxants,2 enzyme inhibitors,3 and surrogates for amides in enzyme mimetics.4 Although amides and carbamates share common features, the additional oxygen of the carbamate functionality exerts unique steric and electronic perturbations. One consequence of this difference is that the barriers to rotation in carbamates are usually 3-4 kcal/mol (about 15-20%) lower than those in the corresponding amides. During a study on the catalysis of cis-trans amide and carbamate isomerization, we observed that the barriers to rotation (∆G‡) in prolyl carbamates were surprisingly insensitive to solvent effects. This behavior contrasts that of amides, where it is common for ∆G‡ to increase by as much as 3 kcal/mol (>100-fold rate decrease) upon a change in environment from a nonpolar, non-hydrogen bonding solvent to water.5 In this paper, we report the first systematic investigation of solvent effects on ∆G‡ for hindered C-N bond rotation in carbamates and that this process occurs with a negative ∆S‡ for acyclic tertiary carbamates in aqueous solution. We began our investigation by studying the effect of solvent on ∆G‡ for the interconversion of the cis and trans forms of the related proline derivatives 1 and 2 (eq 1). The