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PubMed2001

Expedient asymmetric synthesis of all four isomers of N,N'-protected 2,3-diaminobutanoic acid.

2,3-Diaminobutanoic acid (DAB) is found in several peptide antibiotics, toxins, and biologically active molecules. This paper describes the practical and highly enantioselective synthesis of all four N,N'-protected DAB stereoisomers using an asymmetric Rh(I)-phosphine-catalyzed hydrogenation of isomeric enamides as the key step. Thermal and photochemical isomerization of the enamide hydrogenation substrates coupled with catalyst-geometric isomer pairing allows targeted synthesis of single DAB isomers in maximum yield.

Journal Article↗
PubMed1993

The use of tributylphosphine and 4-(aminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole in the study of protein sulfhydryls and disulfides.

The use of the reagent tributyl phosphine (Bu3P) to reduce disulfides (Ruegg, U.T., and Rudinger, J., Methods Enzymol. 47, 111-116, 1977) and of 4-(aminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole (ABD-F) to block free sulphydryl groups (Toyo'oka, T., and Imai, K. Anal. Chem. 56, 2461-2464, 1984) is well established in the literature. Since the two reagents apparently do not react with each other, their combination offers a convenient and quite general method for the complete characterization of free Cys (SH) and crosslinked Cys (S-S) in proteins (Kirley, T.L., J. Biol. Chem. 264, 7185-7192, 1989). We review some of the characteristics of the reaction of these reagents with Cys in peptides and proteins and some of the properties of the ABD-Cys derivatives. The review includes reactions with model compounds (e.g., Cys and glutathione), proteins such as enolase from yeast and rabbit muscle, containing only free Cys, a protein, fetuin, containing only crosslinked Cys, and a protein, superoxide dismutase, containing both free and crosslinked Cys. In all cases the direct comparison of the tryptic or chymotryptic peptides derived from the products of parallel reactions of the protein with ABD-F alone and with ABD-F together with Bu3P permitted the determination of both free and total Cys in the protein. Sequencing the fluorescent ABD-peptides established the position of the Cys residues in the primary sequence.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2006

Resolution of chiral phosphate, phosphonate, and phosphinate esters by an enantioselective enzyme library.

An array of 16 enantiomeric pairs of chiral phosphate, phosphonate, and phosphinate esters was used to establish the breadth of the stereoselective discrimination inherent within the bacterial phosphotriesterase and 15 mutant enzymes. For each substrate, the leaving group was 4-hydroxyacetophenone while the other two groups attached to the phosphorus core consisted of an asymmetric mixture of methyl, methoxy, ethyl, ethoxy, isopropoxy, phenyl, phenoxy, cyclohexyl, and cyclohexoxy substituents. For the wild-type enzyme, the relative rates of hydrolysis for the two enantiomers ranged from 3 to 5.4 x 10(5). Various combinations of site-specific mutations within the active site were used to create modified enzymes with alterations in their enantioselective properties. For the single-site mutant enzyme, G60A, the stereoselectivity is enhanced relative to that of the wild-type enzyme by 1-3 orders of magnitude. Additional mutants were obtained where the stereoselectivity is inverted relative to the wild-type enzyme for 13 of the 16 pairs of enantiomers tested for this investigation. The most dramatic example was obtained for the hydrolysis of 4-acetylphenyl methyl phenyl phosphate. The G60A mutant preferentially hydrolyzes the SP-enantiomer by a factor of 3.7 x 10(5). The I106G/F132G/H257Y mutant preferentially hydrolyzes the RP-enantiomer by a factor of 9.7 x 10(2). This represents an enantioselective discrimination of 3.6 x 10(8) between these two mutants, with a total of only four amino acid changes. The rate differential between the two enantiomers for any given mutant enzyme is postulated to be governed by the degree of nonproductive binding within the enzyme active site and stabilization of the transition state. This hypothesis is supported by computational docking of the high-energy, pentavalent form of the substrates to modeled structures of the mutant enzyme; the energies of the docked transition-state analogues qualitatively capture the enantiomeric preferences of the various mutants for the different substrates. These results demonstrate that the catalytic properties of the wild-type phosphotriesterase can be exploited for the kinetic resolution of a wide range of phosphate, phosphonate, and phosphinate esters and that the active site of this enzyme is remarkably amenable to structural perturbations via amino acid substitution.

Amino Acid Substitution↗
PubMed2003

Novel synthetic method of phosphonamidate peptides and its application in peptide sequencing via multistage mass spectrometry.

Phosphonamidate peptides were prepared in good yields by reaction of ethoxy(phenyl)phosphinate with free peptides in a mixed solution of H2O, C2H5OH, Et3N and CCl4 at room temp.; their in situ electrospray ionization mass spectra exhibited high sensitivity compared with the free peptides, and sequential loss of amino acid residues of the sodiated phosphonamidate peptides from the C-terminus was found in multistage ESI mass spectrometry. The results show that N-phosphonyl derivatization combined with multistage ESI-MS is a powerful method for peptide sequencing.

Amides↗
PubMed2000

Efficient conjugation of peptides to oligonucleotides by "native ligation".

A new strategy has been developed for conjugation of peptides to oligonucleotides. The method is based on the "native ligation" of an N-terminal thioester-functionalized peptide to a 5'-cysteinyl oligonucleotide. Two new reagents were synthesized for use in solid-phase peptide and oligonucleotide synthesis, respectively. Pentafluorophenyl S-benzylthiosuccinate was used in the final coupling step in standard Fmoc-based solid-phase peptide assembly. Deprotection with trifluoracetic acid generated in solution peptides substituted with an N-terminal S-benzylthiosuccinyl moiety. O-trans-4-(N-alpha-Fmoc-S-tert-butylsulfenyl-L-cysteinyl)aminoc yclohe xyl O-2-cyanoethyl-N,N-diisopropylphosphoramidite was used in the final coupling step in standard phosphoramidite solid-phase oligonucleotide assembly. Deprotection with aqueous ammonia solution generated in solution 5'-S-tert-butylsulfenyl-L-cysteinyl functionalized oligonucleotides. Functionalized peptides and oligonucleotides were used without purification in native ligation conjugation reactions in aqueous/organic solution using tris-(2-carboxyethyl)phosphine to remove the tert-butylsulfenyl group in situ and thiophenol as a conjugation enhancer. A range of peptide-oligonucleotide conjugates were prepared by this route and purified by reversed-phase HPLC.

Amino Acid Sequence↗
PubMed2001

Determination of the disulfide structure of sillucin, a highly knotted, cysteine-rich peptide, by cyanylation/cleavage mass mapping.

The disulfide structure of sillucin, a highly knotted, cysteine-rich, antimicrobial peptide, isolated from Rhizomucor pusillus, has been determined to be Cys2--Cys7, Cys12--Cys24, Cys13--Cys30, and Cys14--Cys21 by disulfide mass mapping based on partial reduction and CN-induced cleavage enabled by cyanylation. The denatured 30-residue peptide was subjected to partial reduction by tris(2-carboxyethyl)phosphine hydrochloride at pH 3 to produce a mixture of partially reduced sillucin species; the nascent sulfhydryl groups were immediately cyanylated by 1-cyano-4-(dimethylamino)pyridinium tetrafluoroborate. The cyanylated species, separated and collected during reversed phase high-performance liquid chromatography, were treated with aqueous ammonia, which cleaved the peptide chain on the N-terminal side of cyanylated cysteine residues. The CN-induced cleavage mixture was analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry before and after complete reduction of residual disulfide bonds in partially reduced and cyanylated species to mass map the truncated peptides to the sequence. Because the masses of the CN-induced cleavage fragments of both singly and doubly reduced and cyanylated sillucin are related to the linkages of the disulfide bonds in the original molecule, the presence of certain truncated peptide(s) can be used to positively identify the linkage of a specific disulfide bond or exclude the presence of other possible linkages.

Amino Acid Sequence↗
PubMed1999

Capillary electrophoresis of 99mtechnetium radiopharmaceuticals.

Diagnostically used 99mTc kit radiopharmaceuticals were analyzed using capillary zone electrophoresis with radioactivity detection: 99mTc-bis(bis(2-ethyloxyethyl)phosphino)ethane (99mTc-Myoview, 99mTc-Tetrofosmin), 99mTc-trans(1,2-bis(dehydro-2,2,5,5,-tetramethyl-3-furanone-4-methylene- amino)ethane)-tris(3-methoxy-1-propyl)phosphine) (99mTc-Technescan Q12, 99mTc-Furifosmin), 99mTc-methoxyisobutylisonitrile (99mTc-MIBI), 99mTc-L,L-ethylenecysteine diethylester dimer (99mTc-ECD), 99mTc-d,1-hexamethylene propyleneamine oxime (99mTc-HMPAO), 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA), 99mTc-ethylene hepatobiliary iminodiacetic acid (99mTc-EHIDA), 99mTc-L,L-ethylenecysteine dimer (99mTc-EC), 99mTc-mercaptoacetylglycylglycylglycine (99mTc-MAG3), 99mTc-dimercaptosuccinic acid (99mTc-DMSA), 99mTc-methylene diphosphonate (99mTc-MDP) and 99mNaTcO4. A pressure-driven capillary zone electrophoresis was employed to detect small anions of high electrophoretic mobility and cations within one run. Effective 99mTc complex charges could be determined by a neutral internal standard. All complexes showed the expected electrophoretic behaviours in view of their charges. Pure products were obtained for the majority of the studied complexes. In the case of 99mTc-Q12, 99mTc-EHIDA and 99mTc-MDP, complex mixtures were detected. The high potential of CE for the analysis of 99mTc radiopharmaceuticals could be shown.

Anions↗
PubMed2001

Disulfide bond structure of the AVR9 elicitor of the fungal tomato pathogen Cladosporium fulvum: evidence for a cystine knot.

Disease resistance in plants is commonly activated by the product of an avirulence (Avr) gene of a pathogen after interaction with the product of a matching resistance (R) gene in the host. In susceptible plants, Avr products might function as virulence or pathogenicity factors. The AVR9 elicitor from the fungus Cladosporium fulvum induces defense responses in tomato plants carrying the Cf-9 resistance gene. This 28-residue beta-sheet AVR9 peptide contains three disulfide bridges, which were identified in this study as Cys2-Cys16, Cys6-Cys19, and Cys12-Cys26. For this purpose, AVR9 was partially reduced, and the thiol groups of newly formed cysteines were modified to prevent reactions with disulfides. After HPLC purification, the partially reduced peptides were sequenced to determine the positions of the modified cysteines, which originated from the reduced disulfide bridge(s). All steps involving molecules with free thiol groups were performed at low pH to suppress disulfide scrambling. For that reason, cysteine modification by N-ethylmaleimide was preferred over modification by iodoacetamide. Upon (partial) reduction of native AVR9, the Cys2-Cys16 bridge opened selectively. The resulting molecule was further reduced to two one-bridge intermediates, which were subsequently completely reduced. The (partially) reduced cysteine-modified AVR9 species showed little or no necrosis-inducing activity, demonstrating the importance of the disulfide bridges for biological activity. Based on peptide length and cysteine spacing, it was previously suggested that AVR9 isa cystine-knotted peptide. Now, we have proven that the bridging pattern of AVR9 is indeed identical to that of cystine-knotted peptides. Moreover, NMR data obtained for AVR9 show that it is structurally closely related to the cystine-knotted carboxypeptidase inhibitor. However, AVR9 does not show any carboxypeptidase inhibiting activity, indicating that the cystine-knot fold is a commonly occurring motif with varying biological functions.

Alkylation↗
PubMed2003

P(RNCH2CH2)3N: catalysts for the head-to-tail dimerization of methyl acrylate.

The dimerization of methyl acrylate to the head-to-tail 2-methylene-pentanedioic acid dimethyl ester product was realized in 82 and 85% yield in only 4 h at room temperature in THF in the presence of catalytic amounts of P(RNCH2CH2)3N (R = i-Bu and Bn, respectively). These phosphines are to our knowledge the best nonmetallic catalysts so far reported for this reaction. In contrast, less sterically hindered P(MeNCH2CH2)3N failed to catalyze this dimerization, giving oligomer or polymer instead.

Journal Article↗
PubMed1995

Peptide synthesis using unprotected peptides through orthogonal coupling methods.

We describe an approach to the synthesis of peptides from segments bearing no protecting groups through an orthogonal coupling method to capture the acyl segment as a thioester that then undergoes an intramolecular acyl transfer to the amine component with formation of a peptide bond. Two orthogonal coupling methods to give the covalent ester intermediate were achieved by either a thiol-thioester exchange mediated by a trialkylphosphine and an alkylthiol or a thioesterification by C alpha-thiocarboxylic acid reacting with a beta-bromo amino acid. With this approach, unprotected segments ranging from 4 to 37 residues were coupled to aqueous solution to give free peptides up to 54 residues long with high efficiency.

Acylation↗
PubMed2003

Amplification of a reactive oxygen species signal in axotomized retinal ganglion cells.

Retinal ganglion cells (RGCs) undergo apoptosis after axonal injury. Elucidation of the sequence of intracellular events proximal to caspase activation may allow development of effective neuroprotective strategies. In this study, we explored the role that reactive oxygen species may have in signaling RGC apoptosis after axonal injury. Using the fluorescent probe dihydroethidium, we were able to measure intracellular superoxide anion production. We found that axotomized RGCs exposed to oxidative stress exhibited a secondary superoxide burst. The broad-spectrum caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethyl ketone did not block the burst, suggesting it is proximal to caspase activation, but it was inhibited by cycloheximide, consistent with a requirement for protein synthesis. These results are consistent with RGC axotomy inducing synthesis of one or more proteins that mediate oxidative amplification. This could be an early event in signaling of RGC apoptosis after axonal injury.

Amino Acid Chloromethyl Ketones↗
PubMed2005

Synthesis and biological study of a flavone acetic acid analogue containing an azido reporting group designed as a multifunctional binding site probe.

Flavone-8-acetic acid (FAA) is a potent immunomodulatory small molecule that is uniquely characterized as being active on mouse but not human cells. Although FAA is a potent inducer of murine cytokine, chemokine and interferon gene expression, its mode of action remains unknown. In this report, we describe the synthesis of a new flavone acetic acid (FAA) analogue, (2-[2-(4-azidophenyl)-4-oxochromen-8-yl-]acetic acid (compound 2). We demonstrate that compound 2 is equally active as the parent FAA in inducing chemokine gene expression and that the azide functional group is capable of reacting with a reporter molecule, such as the FLAG peptide-phosphine, under mild conditions. This reaction will be useful for detecting the drug-bound protein active complex utilizing an anti-FLAG antibody.

Animals↗
PubMedDate not supplied

A computational study of the effectiveness of the frontier molecular orbital formalism in predicting conformational isomerism in (p-RC6H4NC)2W(dppe)2.

Ab initio electronic structure calculations on a series of ligands, p-RC6H4NC:, indicate, that the energy of the LUMO correlates with the electron-withdrawing/donating capabilities of the substituent group, which determines the relative pi-acidity of the ligand. Depending on the nature of the para substituent group on the aryl isocyanide ligand, bis(aryl isocyanide) complexes of tungsten-containing bulky bidentate arylphosphine ligands adopt either cis or trans conformations. The frontier molecular orbital formalism predicts that strong pi-acids, which contain electron-withdrawing groups, tend to polarize sufficient charge density away from the metal center to effect the formation of the sterically less favorable but electronically stabilized cis conformer. Density functional theory calculations on similar complexes containing phosphines which do not impose severe steric contraints indicate that the balance between steric and electronic stabilization can be effectively predicted by comparing the relative energies of the ligand LUMOs.

Journal Article↗
PubMed2002

Unexpected hydrodeiodo Sonogashira-Heck-Casser coupling reaction of 2,2'-diiodobiphenyls with acetylenes.

2,2'-Diiodobiphenyl-4,4'-dicarboxylic acid dimethyl ester (3) undergoes either a ring-closure reaction with phenylacetylene to give 4 or hydrodeiodo phenylethynylation to give 5 under the catalytic conditions of Pd(OAc)(2)/CuI/phosphine in amines. In these reactions, the amine and the phosphine ligands play important roles in controlling the reactivity. Among the ligands we used, tris(o-tolyl)phosphine is the best ligand for hydrodeiodo phenylethynylation, while the bidentate phosphine ligand retards both of the reactions. On the basis of our results, we propose that 5 is formed through a fast hydrodeiodination, followed by a Sonogashira phenylethynylation. The results of the deuterium labeling experiments show that proton exchange between the acetylenic proton and the alkyl protons of amine occurs effectively under the reaction conditions. In addition, the hydrogen that replaces the iodide in the hydrodeiodination process arises mainly from the acetylenic proton.

Journal Article↗
PubMed1997

Antiproliferative Hybrid Analogs of the Hormone 1alpha,25-Dihydroxyvitamin D(3): Design, Synthesis, and Preliminary Biological Evaluation.

The combination of 10-12 kbar pressure plus Lewis acidic zinc dichloride promotes highly regioselective and stereoselective Diels-Alder cycloaddition between 3-bromo-2-pyrone, prepared in a new way, and unactivated terminal alkene 4-(tert-butyldimethylsiloxy)-1-butene. The conjugate base of A-ring allylic phosphine oxide 20 adds chemospecifically to the C-8 keto group of some C-8,C-24-diketones to form directly metabolically resistant 24-oxo analogs of 1alpha,25-dihydroxyvitamin D(3) (calcitriol). Several of these new hybrid analogs are as efficacious in vitro as calcitriol at inhibiting growth of murine keratinocytes even at physiologically relevant 10-100 nanomolar concentrations.

Journal Article↗
PubMed2002

Quantifying the electronic effect of substituted phosphine ligands via molecular electrostatic potential.

Values of the molecular electrostatic potential minimum (V(min)) corresponding to the lone pair region of several substituted phosphine ligands (PR(3)) have been determined at the DFT level. The V(min) value is proposed as a quantitative measure of the electronic effect of the PR(3) ligands. Good linear correlation between V(min) and Tolman electronic parameter of PR(3) has been obtained. V(min) is also proportional to the pK(a) values of the conjugate acids of PR(3), viz., [PR(3)H](+). Further, the DeltaE values of the reaction Ni(CO)(3) + PR(3) --> Ni(CO)(3)PR(3) and ScH(3) + PR(3) --> ScH(3)PR(3) are also linearly proportional to the V(min) values. However, if there is a strong metal to phosphorus pi-back-bonding, the DeltaE and V(min) do not fit to a line. It is also found that the standard reduction potential as well as the enthalpy change corresponding to the electrochemical couple eta-Cp(CO)(PR(3))(COMe)Fe(+)/eta-Cp(CO)(PR(3))(COMe)Fe(0) is linearly proportional to the V(min) values of PR(3). These correlations suggest that V(min) is a quantitative measure of the sigma-donating ability of the phosphine. It is hoped that, in phosphine-metal coordination chemistry, the V(min) based electronic parameter could be more advantageous than nu-CO and pK(a) based electronic parameters as it solely represents the inherent electronic property of the ligand.

Journal Article↗
PubMed2002

Phosphinoferrocenylaminophosphines as novel and practical ligands for asymmetric catalysis.

[structure: see text] A new series of ligands with a novel phosphine-aminophosphine ligation design as depicted in structure 1 has been prepared on a ferrocenylethyl backbone. These BoPhoz ligands of structure 2 have afforded exceedingly high activity and enantioselectivity in the rhodium-catalyzed asymmetric hydrogenation of dehydro-alpha-amino acid derivatives, itaconic acids, and alpha-ketoesters. These air-stable ligands are readily prepared from cost-effective and non-pyrophoric intermediates.

Journal Article↗
PubMed2002

Synthesis, characterization, and reactivity of monomeric, arylpalladium halide complexes with a hindered phosphine as the only dative ligand.

We report the isolation and structural characterization of several monomeric arylpalladium(II) halide complexes containing tri-tert-butyl phosphine, 1-adamantyl-di-tert-butylphosphine, or 2-adamantyl-di-tert-butylphosphine. X-ray diffraction, IR spectroscopy, and theoretical studies indicated that the complexes may be stabilized by agostic interactions. For example, the distance from the closest hydrogen atom to the palladium metal center in the X-ray structure of the 1-adamantyl-phenylpalladium bromide complex 1 was 2.26(3) A. The calculated Pd-H distance of 2.28 A and harmonic vibrational frequencies were in agreement with the measured distance, but Wiberg bond indices indicated only weak M-H-C interactions. Addition of 2-adamantyl-di-tert-butyl phosphine to 1 led to ligand exchange and formation of 2-adamantyl-di-tert-butyl phosphine complex 2. Addition of P(t-Bu)(3) generated free aryl bromide and Pd[P(t-Bu)(3)](2). Reactivity of complex 1 with nucleophiles provided evidence of the intermediacy of these complexes in palladium-catalyzed cross-coupling reactions. Complex 1 reacted with amine and base to form the corresponding arylamine, with tert-butoxide to form the corresponding ether, with boronic acid and fluoride to form the corresponding biaryl, and with styrene to form stilbene. This complex also catalyzed the reaction of bromobenzene with diphenylamine in the presence of base to produce 94% of the amination product in 45 min at room temperature. This rate is comparable to the reaction rate of in situ generated catalysts.

Halogens↗