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PubMed1988

Mechanism-based inactivation of horseradish peroxidase by sodium azide. Formation of meso-azidoprotoporphyrin IX.

Catalytic turnover of sodium azide by horseradish peroxidase, which produces the azidyl radical, results in inactivation of the enzyme with KI = 1.47 mM and kinact = 0.69 min-1. Inactivation of 80% of the enzyme requires approximately 60 equiv each of NaN3 and H2O2. The enzyme is completely inactivated by higher concentrations of these two agents. meso-Azidoheme as well as some residual heme are obtained when the prosthetic group of the partially inactivated enzyme is isolated and characterized. Reconstitution of horseradish peroxidase with meso-azidoheme yields an enzyme without detectable catalytic activity even though reconstitution with heme itself gives fully active enzyme. The finding that catalytically generated nitrogen radicals add to the meso carbon of heme shows that biological meso additions are not restricted to carbon radicals. The analogous addition of oxygen radicals may trigger the normal and/or pathological degradation of heme.

Azides↗
PubMed1989

Detection of nearest neighbors to specific fluorescently tagged ligands in rod outer segment and lymphocyte plasma membranes by photosensitization of 5-iodonaphthyl 1-azide.

Lima bean agglutinin-fluorescein 5-isothiocyanate conjugate (FluNCS-lima bean lectin) interacts with specific receptor molecules on membranes both from the rod outer segment (ROS) of the frog retina and from S49 mouse lymphoma cells. When [125I]-5-iodonaphthyl 1-azide (125I-INA), which freely and randomly partitions into the lipid bilayer, is added to membranes and the suspension is irradiated at 480 nm, the FluNCS-conjugated lectin photosensitizes the [125I]INA but only at discrete sites. This results in the selective labeling of specific proteins: an 88-kDa protein on ROS membranes and a 56-kDa protein on S49 plasma membranes. Labeling is dependent upon the interaction of the FluNCS-lectin with glycosylated receptor sites, since N-acetylgalactosamine, but not methyl alpha-mannoside, blocked labeling of the 56-kDa protein on S49 membranes. In contrast, a random labeling pattern of membrane proteins was observed upon irradiation at 480 nm using other fluorescein conjugates, such as FluNCS-bovine serum albumin (FluNCS-BSA) or FluNCS-soybean trypsin inhibitor (FluNCS-STI), which interact with cell membranes in a nonselective manner, or with N-(fluorescein-5-thiocarbamoyl)-n-undecyclamine (FluNCS-NHC11), which is freely miscible in the membrane lipid. Random labeling was also obtained by direct photoexcitation of [125I]INA at 314 nm, with no distinct labeling of the 88- and 56-kDa proteins in the respective membranes. These results suggest that protein ligands can be used to guide sensitizers to discrete receptor sites and lead to their selective labeling by photosensitized activation of [125I]INA [Raviv, Y., Salomon, Y., Gitler, C., & Bercovici, T. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 6103-6107].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Interactions of wild-type and mutant M protein of vesicular stomatitis virus with viral nucleocapsid and envelope in intact virions. Evidence from [125I]iodonaphthyl azide labeling and specific cross-linking.

Four different temperature-sensitive M protein mutants (tsM) of vesicular stomatitis virus (VSV) were characterized with regard to the association of the mutated M protein either with nucleocapsids or with membranes in the intact virions. Virions were labeled with the photoreactive hydrophobic probe [125I]iodonaphthyl azide (INA) to assess interactions between viral proteins and the lipid envelope. In wild type (wt) virions, the three major structural proteins--G, M, and N--were labeled in the ratio ca. 1.0:0.4:0.2. INA labeled only the membrane-associated peptide of G protein, both in the intact virion and in reconstituted G protein--viral lipid vesicles, demonstrating the specificity of INA for lipid bilayer regions. Labeling of tsM virions with INA resulted in a 2--3-fold greater incorporation into M protein than was found for wt virions, suggesting increased M--membrane associations in the mutant virions. Temperature-stable revertants from tsM possessed wt labeling characteristics. Interaction of the M protein with nucleocapsids was assessed from the abundance of disulfide-linked M--N complexes found after disruption of the virions by sodium dodecyl sulfate solution under nonreducing conditions. The abundance of such complexes was 30--80% less from tsM virions than from wt virions, suggesting decreased M--nucleocapsid interactions in tsM virions. Temperature-stable revertants from tsM resembled wt in the abundance of M--N complex formed. We conclude that the mutations alter M protein in such a way as simultaneously to increase its association with membrane and to decrease its affinity for nucleocapsids in the intact virion.

Animals↗
PubMed1975

The binding of azide to human methemoglobin A0. Error analysis for the interpolative and noninterpolative methods.

The binding azide to human methemoglobin A0 has been studied at 6 degrees, pH 7, and I = 0.2 by three spectroscopic methods: (1) the conventional interpolative method, (2) an interpolative dialysis technique, and (3) a noninterpolative method. The interpolative methods assume that the fractional spectral change equals the fraction of heme sites bound by ligand, while the noninterpolative method measures the extent of binding directly, i.e., without the interpolative assumption. Both experiment and error analysis show that method 1 has low precision, and consequently, gives an inherently unreliable binding isotherm. Method 2 achieves high experimental and intrinsic precision. However, method 3, which also has high precision, clearly proves that the interpolative assumption of method 2 is incorrect. That is, the true fractional extent of binding becomes equal to the fractional spectral change only after about 97% of heme sites have been bound with ligands.

Azides↗
PubMed2005

Probing the geometric and electronic structures of the low-temperature azide adduct and the product-inhibited form of oxidized manganese superoxide dismutase.

The geometric and electronic structures of the six-coordinate azide adduct of oxidized manganese superoxide dismutase (Mn3+ SOD) that is formed at low temperatures, LT N3-Mn3+ SOD, has been examined in detail through a combined spectroscopic/computational approach. Electronic absorption, circular dichroism (CD), magnetic CD (MCD) and variable-temperature, variable-field (VTVH) MCD spectroscopies were used to determine electronic transition energies and to obtain an estimate of zero-field splitting parameters for LT N3-Mn3+ SOD. These experimental data were utilized in conjunction with semiempirical intermediate neglect of differential overlap/spectroscopic parametrization-configuration interaction (INDO/S-CI) and time-dependent density functional theory (TD-DFT) computations to evaluate hypothetical active-site models of LT N3-Mn3+ SOD generated by constrained DFT geometry optimizations. Collectively, our spectroscopic/computational results indicate that N3- binding to Mn3+ SOD at low temperatures promotes neither protonation of the axial solvent ligand nor reorientation of the redox-active molecular orbital, both of which had been previously suggested. Using the same experimentally validated computational approach, models of the product-inhibited form of MnSOD were also developed and evaluated by their relative energies and TD-DFT-computed absorption spectra. On the basis of our computational results as well as previously published kinetic data, we propose that the product-inhibited form of MnSOD is best described as a side-on peroxo-Mn3+ adduct possessing an axial H2O ligand. Notably, attempts to generate a stable hydroperoxo-Mn3+ SOD species by protonation of the proximal O atom of the hydroperoxo ligand resulted in dissociation of HOO- and eventual H+ transfer from Tyr34 to HOO-, generating deprotonated Tyr34 and H2O2. The implications of these results with respect to the mechanism of O2*- dismutation by MnSOD are discussed.

Azides↗
PubMed1997

Conformational changes and fusion activity of vesicular stomatitis virus glycoprotein: [125I]iodonaphthyl azide photolabeling studies in biological membranes.

The interaction of VSV glycoprotein (VSV G) with biological membranes was studied by photosensitized labeling. The method is based on photosensitized activation by the fluorescent lipid analog 3,3'-dioctadecyloxacarbocyanine (DiO) of a hydrophobic probe, [125I]iodonaphthyl azide (125INA), that rapidly partitions into the membrane bilayer of virus and cells. 125INA labeling of proteins and lipids can be confined to the site of chromophore localization by photosensitized labeling. Photoactivation using visible light of target membrane labeled with DiO and 125INA, to which unlabeled virions are bound, results in exclusive labeling of envelope glycoproteins inserted into the target membrane [Pak et al. (1994) J. Biol. Chem. 269, 14614]. In this study, we labeled lipid symmetric erythrocyte ghosts with 125INA and DiO. Photosensitized activation of VSV prebound to labeled ghosts with visible light resulted in VSV G labeling under fusogenic conditions. Photoactivation of 125INA by UV light, which is nonspecific, produced labeled VSV G at both acidic and neutral pH. Photosensitized labeling of VSV G by DiO-125INA-ghosts was also observed at pH 5.5, 4 degrees C, in the absence of mixing between viral and cellular lipids, suggesting insertion of the ectodomain of VSV G. Soluble VSV G lacking the transmembrane domain inserted into DiO-125INA-ghosts under the same conditions as intact VSV G. DiO inserted into intact VSV appeared to be a suitable fluorophore for continuous kinetic measurements of membrane fusion by fluorescence dequenching. Our photosensitized labeling results establish biochemical correlates for the three states of VSV G, which we had proposed based on kinetic data [Clague et al., Biochemistry 29, 1303]. In addition, we found that VSV G insertion into the target membrane is reversible, suggesting a "velcro"-like attachment of the fusogenic domain with the target membrane.

Affinity Labels↗
PubMed2005

Kinetic and donor stabilization of organotellurenyl iodides and azides.

The first tellurium compounds containing the extremely bulky tris(phenyldimethylsilyl)methyl (Tpsi) and 2,6-bis(2,4,6-triisopropylphenyl)phenyl (2,6-Trip(2)C(6)H(3)) moieties have been synthesized and isolated. Careful oxidation of the tellurolate TpsiTeLi (1) resulted in the formation of the crowded ditellane (TpsiTe)(2) (2), and iodination of 2 gave the alkanetellurenyl iodide TpsiTeI (3). In a similar fashion, the terphenyl-substituted ditellane (2,6-Trip(2)C(6)H(3)Te)(2) (9) and the arenetellurenyl iodide 2,6-Trip(2)C(6)H(3)TeI (10) were prepared. Reaction of the iodides TpsiTeI (3) and 2,6-Trip(2)C(6)H(3)TeI (10), as well as TripTeI, MesTeI (Trip = 2,4,6-triisopropylphenyl, Mes = 2,4,6-tri-tert-butylphenyl), and the donor-stabilized 2-Me(2)NCH(2)C(6)H(4)TeI, with AgN(3) resulted in the formation and isolation of the corresponding tellurenyl azides TpsiTeN(3) (4), TripTeN(3) (7), MesTeN(3) (8), 2,6-Trip(2)C(6)H(3)TeN(3) (11), and 2-Me(2)NCH(2)C(6)H(4)TeN(3) (12). Furthermore, the corresponding tris(ethyldimethylsilyl)methyl-containing (Tesi) tellurium compounds (TesiTe)(2), TesiTeI (5), and TesiTeN(3) (6) have been prepared but could not be isolated in pure form. The crystal structures of TpsiTeLi (1), (TpsiTe)(2) (2), TpsiTeN(3) (4), 2,6-Trip(2)C(6)H(3)TeI (10), 2,6-Trip(2)C(6)H(3)TeN(3) (11), and 2-Me(2)NCH(2)C(6)H(4)TeN(3) (12) have been determined by X-ray diffraction. Additionally, computational studies of the molecules for which experimental structural data were available were performed.

Azides↗
PubMed2003

Stereoselective synthesis of alpha- and beta-glycosylamide derivatives from glycopyranosyl azides via isoxazoline intermediates.

Treatment of 2-acetoxy glycopyranosyl azides with Ph3P gave isoxazolines by ring closure of the phosphorimine. Coupling of in situ generated isoxazolines with acylating reagents gave mixtures of alpha- or beta-glycopyranosyl amides. The alpha/beta ratio depended upon the acylating reagent and metal salts employed. For example, coupling of isoxazoline 3 with Z-Asp-(SPy)-OBn in the presence of CuCl2 gave exclusively alpha-N-glucopyranosylasparagine derivative 8. This general procedure has been applied to mono-, di-, and trisaccharide systems.

Amino Acid Sequence↗
PubMed2003

The reaction of thio acids with azides: a new mechanism and new synthetic applications.

A new amide synthesis strategy based on a fundamental mechanistic revision of the reaction of thio acids and organic azides is presented. The data demonstrate that amines are not formed as intermediates in this reaction. Alternative mechanisms proceeding through a thiatriazoline intermediate are suggested. The reaction has been applied to the preparation of simple and architecturally complex amides that are difficult to access using conventional methods. The reaction is chemoselective, effective for unprotected substrates, and compatible with aprotic and protic solvents, including water.

Amides↗
PubMed2005

Highly efficient one-pot synthesis of N-sulfonylamidines by Cu-catalyzed three-component coupling of sulfonyl azide, alkyne, and amine.

A highly efficient, mild, practical, and catalytic multicomponent reaction for the synthesis of N-sulfonylamidines has been developed. This reaction has an extremely wide scope with regard to all three coupling components of alkyne, sulfonyl azide, and amine. Two plausible mechanistic pathways involving ketenimine or triazole intermediate are tentatively presented for the copper-catalyzed three-component coupling reactions.

Alkynes↗
PubMed2005

Ruthenium-catalyzed cycloaddition of alkynes and organic azides.

Cp*RuCl(PPh3)2 is an effective catalyst for the regioselective "fusion" of organic azides and terminal alkynes, producing 1,5-disubstituted 1,2,3-triazoles. Internal alkynes also participate in this catalysis, resulting in fully substituted 1,2,3-triazoles.

Acetylene↗
PubMed2006

Organic azide inhibitors of cysteine proteases.

Cysteine proteases are crucial regulatory enzymes in human physiology and disease. Inhibitors are usually designed with reactive electrophiles to covalently bond to the catalytic cysteinyl sulfur, and consequently they also indiscriminately interact with biological thiolates and other nucleophiles, leading to toxic side effects in vivo. Here we describe an alternative to using reactive electrophiles, demonstrating the use of a much less reactive azidomethylene substituent (-CH2-N3) that confers potent inhibition of cysteine proteases. This new approach resulted in potent, reversible, competitive inhibitors of caspase-1 (IC50 < 10 nM), with significant advantages over aldehydes such as high stability in vitro to thiols (10 mM dithiothreitol (pH 7.2), 20 mM glutathione (pH 7.2, 9, 11)) and aqueous media, as well as some highly desirable druglike features. It was also demonstrated that azides can be incorporated into inhibitors of other caspases (e.g. 3, 8) and cathepsins (e.g. K, S, B), indicating the versatility of this valuable new approach to cysteine protease inhibition.

Aldehydes↗
PubMed1981

Some reactions of 1,4-dihydropyridines with organic azides. Synthesis of 2,7-diazabicyclo[4.1.0]hept-3-enes with analgesic and antiprotozoal activity.

The 1,3-dipolar cycloaddition reaction of 1,4-dihydropyridines, 2, with organic azides, 3, afford 2,7-diazabicyclo[4.1.0]hept-3-enes, 4, which exhibit significant analgesic and antiprotozoal activities. The most active analgesics, 4a and 4c, were more potent than aspirin or dextropropoxyphene. Diazabicyclo[4.1.0]hept-3-enes 4a-e exert potent antiprotozoal activity, inhibiting growth of Trichomonas vaginalis at concentrations of less than 10 micrograms/mL of medium. The broad spectrum pharmacological screen also revealed moderate hypoglycemic (4a), antiinflammatory (4c), antidepressant (4d and 4e) and antihistaminic (4f) activities.

Analgesics↗
PubMed1988

Photoaffinity labeling adenosine A1 receptors with an antagonist 125I-labeled aryl azide derivative of 8-phenylxanthine.

We have derivatized a series of 125I-labeled 8-phenylxanthines with photoactive aryl azide groups on the 1- or 3-position of the xanthine ring. A 3-azidophenethyl derivative was found to be optimal for use as an antagonist photoaffinity label for adenosine A1 receptors. Following photoactivation, radioactivity was covalently and specifically incorporated into a 34,000-dalton and, to a lesser extent, into a 24,000-dalton polypeptide of rat brain membranes. Photoincorporation into both polypeptides was competitively inhibited by adenosine analogues with a potency order typical of adenosine A1 receptors, but the 24,000-dalton polypeptide bound both agonists and antagonists with lower affinity than the 34,000-dalton polypeptide. Specific photolabeling of receptors in brain membranes of rat, guinea pig, dog, and cow did not show any variation in the 34,000-dalton adenosine receptor binding subunit. The adenosine agonist photoaffinity label [125I]N6-(4-azido-3-iodobenzyl)adenosine also specifically photolabeled the 34,000-dalton polypeptide, but photoincorporation of the agonist was less efficient than the antagonist and, unlike the antagonist, was greatly reduced by guanosine 5'-(beta,gamma-imidotriphosphate). The results indicate that the antagonist photoaffinity label may be more useful than agonists particularly for labeling uncoupled receptors.

Affinity Labels↗
PubMed2000

Synthesis of C-terminal glycopeptides from resin-bound glycosyl azides via a modified Staudinger reaction.

The solid-phase synthesis of glycopeptides containing the sugar at the C-terminus is reported. The method is demonstrated on a model, the endogenous antinociceptive peptide Leu-enkephalin. 2,3,4-Tri-O-acetyl-1-azido-1-deoxy-beta-D-glucopyranuronic acid was synthesized and immobilized onto a variety of derivatized resins. Conjugation of the first amino acid was accomplished by reaction of the resin-bound glycosyl azide with an activated amino acid, in one step, via a modified Staudinger reaction. Standard solid-phase peptide synthesis then resulted in the desired amide-linked glycopeptide. Reaction conditions and reagents for the glycosylation were varied to optimize the yield and purity of the product. The optimum conditions were found to be the use of a 4-fold molar excess of activated amino acid and 3-fold excess of tri-n-butylphosphine in tetrahydrofuran. This methodology is generally applicable to most peptide sequences and is compatible with both Boc- and Fmoc- synthetic strategies on a variety of resins.

Azides↗
PubMed2001

Mimicry of peptide backbone geometry and heteroatomic side-chain functionality: synthesis of enantiopure indolizidin-2-one amino acids possessing alcohol, acid, and azide functional groups.

Indolizidinone amino acids possessing various heteroatomic side chains at their 5- and 7-positions have been synthesized through modification of hydroxymethyl indolizidinone amino acids 5 and 6. Displacements of the methanesulfonates from alcohols 5 and 6 with sodium azide, as well as oxidation of alcohol 5, have been used to furnish orthogonally protected indolizidin-2-one diamino carboxylates 7 and 8, and indolizidin-2-one amino dicarboxylate 9. Both 5- and 7-hydroxymethylindolizidinone amino acids 5 and 6 were obtained from sequences commencing with the Claisen condensation of alpha-tert-butyl gamma-methyl l-N-(PhF)-L-glutamate to furnish di-tert-butyl 4-carbomethoxy-5-oxo-2,8-di-[N-(PhF)amino]azelate 10 (PhF = 9-(9-phenylfluorenyl)). Subsequent hydride reduction of 10 to an isomeric mixture of diols 12, selective protection of the primary alcohol as tert-butyldimethylsilyl ether 14 and oxidation of the secondary alcohol gave di-tert-butyl 4-tert-butyldimethylsilyloxymethyl-5-oxo-2,8-di-[N-(PhF)amino]azelate 15 as a separable diastereomeric mixture. Linear ketone 15 and alcohol 14 were then converted to the indolizidinone heterocycles by routes featuring reductive aminations, methanesulfonate displacements, and lactam cyclizations. A series of rigid scaffolds designed to mimic the conformations of dipeptides possessing serine, lysine, and glutamate residues has thus been synthesized by this new route for installing heteroatomic side-chain functional groups onto the indolizidin-2-one system.

Alcohols↗
PubMed2001

Phosphinic acid pseudopeptides analogous to glutamyl-gamma-glutamate: synthesis and coupling to pteroyl azides leads to potent inhibitors of folylpoly-gamma-glutamate synthetase.

Several routes to a complex phosphinate phosphapeptide analogous to the gamma-glutamyl peptide Glu-gamma-Glu have been investigated. Formation of gamma-phosphono glutamate derivatives via addition of a phosphorus-based radical to protected vinylglycine was found to be of limited value because of the elevated temperatures required. Alkylation and conjugate addition reactions of trivalent phosphorus (P(III)) species were investigated. In situ generation of bis-trimethylsilyl esters of phosphinous acids proved to be an effective route to phosphinates of modest structural complexity. However, this chemistry could not be extended to the incorporation of an amino acid moiety at the N-terminal side of the desired phosphinate. A successful synthesis of the target phosphinate phosphapeptide was effected using P(III) chemistry and dehydrohalogenation to yield an alpha,beta-unsaturated phosphinic acid ester, following which conjugate addition of diethylacetamido malonate and acid-mediated hydrolysis afforded the desired phosphinate phosphapeptide. Coupling of the unprotected phosphinate phosphapeptide with two acyl azides derived from folic acid and methotrexate led to the corresponding pteroylphosphapeptides of interest as possible mimics of tetrahedral intermediates in the reaction catalyzed by folylpolyglutamate synthetase.

Azides↗