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PubMed1994

[NMDA receptor and long-term potentiation].

In order to evaluate the role of the NMDA receptor redox site in long-term potentiation (LTP), we have investigated the effects of two redox reagents, 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) and tris(carboxyethyl)phosphine (TCEP) on the induction and expression of various forms of LTP. DTNB a thiol-oxidizing agent, irreversibly reduces by 50% NMDA receptor EPSP. In the presence of DTNB, the induction of tetanic and anoxic LTP are prevented. When tetanic or anoxic LTP were generated first, DTNB completely reverses the potentiation and TCEP a disulfide-reducing agent restores LTP to its initial level. These redox agents have no effect on AMPA synaptic transmission and did not significantly modify the induction and the expression of tetanic AMPA-LTP. These results suggest that thiol-oxidizing compounds might be useful for the treatment of cerebral ischemia.

Animals↗
PubMed2004

Boron trifluoride-mediated alkylation of diphenylphosphine with tert-alkyl fluoride.

[reaction: see text] Treatment of tertiary alkyl fluoride with diphenylphosphine in the presence of a stoichiometric amount of boron trifluoride etherate yields the corresponding tert-alkyldiphenylphosphine despite the coexistence of the strong Lewis acid and the highly coordinating phosphine. Use of diphenyl(trimethylsilyl)phosphine as a nucleophile makes the reaction catalytic in boron trifluoride.

Journal Article↗
PubMed1997

Synthesis and cystine/cysteine-catalyzed oxidative folding of the amaranth alpha-amylase inhibitor.

We report here the total synthesis of the alpha-amylase inhibitor (AAI), a 32-residue-long peptide with three disulfide bridges, isolated from amaranth seeds (Chagolla-Lopez, A., Blanco-Labra, A., Patthy, A., Sanchez, R. & Pongor S. (1994) J. Biol. Chem. 269, 23675-23680). The synthesis was carried out using a stepwise solid-phase approach based on the Fmoc/t-Bu chemistry, combined with the S-acetamidomethyl protection for cysteines. The linear, reduced peptide was obtained after two reduction steps, using 1,4-dithio-DL-threitol and tri(2-carboxyethyl)phosphine hydrochloride in basic and acidic conditions, respectively. Disulfide bridges were formed by oxidative folding in a cystine/cysteine redox buffer, these conditions were found superior to air oxidation and to glutathione-catalyzed oxidative folding. The physiochemical and enzyme inhibitory properties of synthetic AAI were found identical with those of natural product. Several orthogonal protection schemes proved unsuccessful in obtaining a biologically active product.

Amino Acid Sequence↗
PubMed1996

Development of the first potent and selective inhibitor of the zinc endopeptidase neurolysin using a systematic approach based on combinatorial chemistry of phosphinic peptides.

A new systematic approach, based on combinatorial chemistry of phosphinic peptides, is proposed for rapid development of highly potent and selective inhibitors of zinc metalloproteases. This strategy first evaluates the effects on the inhibitory potency and selectivity of the following parameters: 1) size of the phosphinic peptides, 2) position of the phosphinic bond in the sequence, and 3) the state (free or blocked) of the peptide extremities. After this selection step, the influence of the inhibitor sequence is analyzed in order to determine the identity of the residues that optimized both the potency and the selectivity. We demonstrate the efficiency of this novel approach in rapid identification of the first potent inhibitor of the mammalian zinc endopeptidase neurolysin(24-16), able to discriminate between this enzyme and the related zinc endopeptidase thimet oligopeptidase(24-15). The most potent and selective inhibitor developed in this study, Pro-LPhePsi(PO2CH2)Gly-Pro, displays a Ki value of 4 nM for 24-16 and is 2000 times less potent on 24-15. The specific recognition of such a free phosphinic tetrapeptide by 24-16, as well as the unique specificity of the 24-16 S2 and S2' subsites for proline, unveiled by this study, are discussed in terms of their possible significance for the function of this enzyme and its related zinc endopeptidase activities.

Amino Acid Sequence↗
PubMed2002

Phosphine-stabilized arsenium salts: water-stable, labile, coordination complexes.

A series of air- and water-stable tertiary phosphine-stabilized arsenium salts of the type R(3)P-->AsR(2)(+)PF(6)(-) has been isolated. In the crystal structures of two chiral triarylphosphine complexes of prochiral methylphenylarsenium hexafluorophosphate, the stereochemistry around arsenic is trigonal pyramidal with the phosphorus atom occupying the apical position, the As-P bond being orthogonal to the plane of the trigonal (lone-pair included) arsenium ion: Ph(3)P-->AsMePh(+) PF(6)(-), P2(1)/c, a = 10.7775(2) A, b = 17.7987(3) A, c = 13.3797(2) A, beta = 109.066(1) degrees, V = 2425.78(7) A(3), T = 200 K, Z = 4; Ph(2)(2-MeOC(6)H(4))P-->AsMePh(+) PF(6)(-), P1, a = 10.8077(2) A, b = 10.9741(2) A, c = 13.5648(2) A, alpha = 99.0162(9) degrees, beta = 105.2121(9) degrees, gamma = 116.4717(9) degrees, V = 1318.11(5) A(3), T = 200 K, Z = 2. The arsenium ion in each case appears to be further stabilized by conjugation of the lone pair with the phenyl group, with which the arsenic and methyl-carbon atoms are almost coplanar. In the crystal structure of the 2-(methoxymethylphenyl)diphenylphosphine adduct of methylphenylarsenium hexafluorophosphate, there operates a counteractive chelate effect in which anchimeric oxygen coordination to arsenic destabilizes the arsenic-phosphorus bond in the six-membered chelate ring. Although they are stable, phosphine-stabilized arsenium salts undergo rapid phosphine exchange and attack at arsenic by anionic carbon and oxygen nucleophiles to give tertiary arsines and arsinous acid esters, respectively, with liberation of the phosphine.

Journal Article↗
PubMed1971

New synthetic phosphinate analogues of lecithin.

The chemical syntheses of two new, completely nonhydrolyzable phosphinate analogues of lecithin are described. These have the structures ROCH(2)CH(OR)CH(2)CH(2)P(O)(O(-))CH(2)CH(2)N(+)(CH(3))(3) and ROCH(2)CH(OR')CH(2)P(O)(O(-))CH(2)CH(2)CH(2)N(+)(CH(3))(3), where R = C(18)H(37) and R' = C(16)H(33); each is thus isosteric with lecithin on either side of the phosphorus function. The infrared spectra of these compounds undergo unexpected changes under mild acid, base, or adsorptive treatment. These are discussed and compared with related lecithin analogues, including the simple phosphinate C(18)H(37)P(O)(O(-))CH(2)CH(2)N(+)(CH(3))(3), whose synthesis is also reported.

Chemical Phenomena↗
PubMed2005

Crystal structures of active LytM.

Lysostaphin-type enzymes are metalloendopeptidases that are present in bacteriophages and in bacteria. They share the catalytic domain, but normally contain other domains as well. The well-characterized enzymes in this group are all specific for the pentaglycine crosslinks in the cell walls of some Gram-positive bacterial species. Lysostaphin-type enzymes are synthesized as secreted preproenzymes and require proteolytic activation for maturation. Although lysostaphin, the prototypical peptidase in the group, is widely used as a tool in biotechnology and developed as an antistaphylococcal agent, the detailed structure of this enzyme is unknown. So far, only one lysostaphin-type enzyme, the Staphylococcus aureus autolysin LytM, has been crystallized in its full-length, inactive form. Here, we describe the synthesis of a convenient reporter substrate, characterize the metal and pH-dependence of an active LytM fragment, and present its crystal structure in three crystal forms at different pH values that either support or do not support activity. In all structures, we find an extended, long and narrow groove that has the active site at its bottom and is delineated on the sides by the most flexible regions of the molecule. In two cases, the groove is partially filled by a loop of a neighbouring molecule in the crystal. As the loop contains three consecutive glycine residues, this crystal packing effect supports the interpretation that the groove is the substrate-binding cleft. To characterize the substrate-binding mode more closely, a phosphinate analogue of tetraglycine was synthesized. Although tetraglycine is a substrate of the active LytM fragment, the phosphinate analogue turned out to be a very poor inhibitor. Crystals that were grown in its presence contained an L+-tartrate molecule from the crystallization buffer and not the phosphinate in the active site.

Bacterial Proteins↗
PubMed2006

Binding of phosphinate and phosphonate inhibitors to aspartic proteases: a first-principles study.

Phosphinate and phosphonate derivatives are potent inhibitors of aspartic proteases (APs). The affinity for the enzyme might be caused by the presence of low barrier hydrogen bonds between the ligand and the catalytic Asp dyad in the cleavage site. We have used density functional theory calculations along with hybrid quantum mechanics/molecular mechanics Car-Parrinello molecular dynamics simulations to investigate the hydrogen-bonding pattern at the binding site of the complexes of human immunodeficiency virus type-1 AP and the eukaryotic endothiapepsin and penicillopepsin. Our calculations are in fair agreement with the NMR data available for endothiapepsin (Coates et al. J. Mol. Biol. 2002, 318, 1405-1415) and show that the most stable active site configuration is the diprotonated, negatively charged form. In the viral complex both protons are located at the catalytic Asp dyad, while in the eukaryotic complexes the proton shared by the closest oxygen atoms is located at the phosphinic/phosphonic group.

Aspartic Acid Endopeptidases↗
PubMed1990

New and versatile approaches to the synthesis of CPP-related competitive NMDA antagonists. Preliminary structure-activity relationships and pharmacological evaluation.

Fourteen new CPP analogues have been prepared with methyl 1-(phenylmethyl) (+/-)-1,2-piperazinedicarboxylate 3 as a versatile synthetic intermediate. Derivatives were evaluated as NMDA ligands by their ability to displace [3H]CPP from rat cortical membranes. The binding affinity of various chain lengths at the N4-position of the CPP analogues, 5a, 5b, and 9a mimics the binding affinity observed for the acyclic derivatives AP6, AP8, and AP5. Analogue 9a, with a single methylene group in its phosphonate side chain, exhibited diminished affinity for the NMDA receptor when compared to the structurally similar piperidine compound CGS 19755. Replacement of the phosphonic acid moiety with monoionizable acidic groups such as a carboxylate or a phosphinate resulted in a reduction of binding affinity. An aryl spacer between the N4-nitrogen and the distal acidic group was detrimental to binding as was alkylation at the N1-position. Steric bulk, however, was better tolerated when a phenyl group was positioned alpha to the phosphonate, as seen with analogues 21 and 22.

Animals↗
PubMed1995

Three-dimensional structure of cyclohexapeptides containing a phosphinic bond in aqueous solution: a template for zinc metalloprotease inhibitors. A NMR and restrained molecular dynamics study.

The 3D structures of two phosphinic cyclic hexapeptide inhibitors of bacterial collagenase, cyclo-(Gly1-Pro2-Phe3 psi[PO2-CH2]Gly4-Pro5-Nle6) (compound I) and cyclo(Gly1-Pro2-D-Phe3 psi[PO2-CH2]-Gly4-Pro5-Nle6) (compound II), in aqueous solution, as derived from NMR spectroscopy and molecular dynamics simulations, are described. The general structures of these cyclic hexapeptides closely resemble the "canonic" two-reverse-turn structure, with the proline occupying the (i + 1) position of the turns and the glycine the connecting positions. The phosphinic bond is located between the (i + 2) and (i + 3) positions of one of these turns. However, a striking feature of the backbone structure of these peptides is the presence of double type VIII-turns in compound I, and in compound II of type VIII- and tentatively named type IX-turns. The comparison of the 3D structures of these two cyclic hexapeptides shows that the stereochemistry of the phenylalanylphosphinyl residue influences not only the local conformation but also the global topology of the peptide macrocycle. The differences in the 3D structure of these compounds are discussed in relation to their inhibitory potencies and with the view of using these constrained cyclic peptides as a scaffold for the development of rigid metalloproteases inhibitors.

Amino Acid Sequence↗
PubMed1996

Comparison of four homologous retention index standard series for qualitative gas chromatography of nitrogenous acidic and neutral drugs.

Four homologous retention index standard series, the alkylmethylhydantoins, alkylhydantoins, alkylmaleimides and alkylbis(trifluoromethyl)phosphine sulphides, were evaluated for the screening of blood samples for acidic and neutral drugs on Ultra 2 and HP-1701 capillary columns over a six-month period. An index series consisting of actual drug substances was used as a standard of comparison. All the series produced high precision, and the precision differences between the series were rather small. Considering the limitations of the other series, the alkylmethylhydantoins and alkylhydantoins turned out to be the most feasible internal retention index standard series in the present dual column setting.

Blood Chemical Analysis↗
PubMed2005

Stimulation of intracellular Ca2+ elevation in neutrophils by thiol-oxidizing phenylarsine oxide.

Phenylarsine oxide (PAO), a trivalent arsenical compound, stimulated [Ca2+]i elevation in rat neutrophils in a Ca2+-containing medium but caused no appreciable response in a Ca2+-free medium. PAO also induced external Mn2+ entry, which was inhibited by N-acetyl-L-cysteine (NAC), but failed to elicit any appreciable Ba2+ and Sr2+ entry. Pretreatment of neutrophils with thiol-reducing agents including dithiothreitol (DTT), NAC, 2,3-dimercapto-1-propanol (DMP), 2,3-dimercaptopropane-1-sulfonic acid (DMPS) and tris-(2-carboxyethyl)phosphine (TCEP), all greatly inhibited PAO-induced [Ca2+]i elevation. Addition of Ni2+ or La3+ followed by PAO stimulation also attenuated the Ca2+ signals in a concentration-dependent manner. PAO had no significant effect on the production of reactive oxygen intermediates (ROI) and nitric oxide (NO) nor did it decrease cellular low molecular weight thiols levels. PAO-induced [Ca2+]i elevation was significantly inhibited by 1-[6-[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122), the inhibitor of phospholipase C-coupled processes, genistein, a general tyrosine kinase inhibitor, phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, calyculin A, a cortical actin stabilizer, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002), a phosphoinositide 3-kinase inhibitor, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole (SKF-96365), and cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL-12,330A), the blockers of receptor-gated and store-operated Ca2+ channels, whereas there was no appreciable effect exerted by aristolochic acid, a phospholipase A2 inhibitor, 7-nitroindazole and N-(3-aminomethyl)benzylacetamidine (1400W), the blockers of NO synthase, and by suspension in a Na+-deprived medium. In contrast, 2-aminoethoxydiphenyl borane (2-APB), the blocker of IP3 receptor and Ca2+ influx, enhanced the PAO-induced response. PAO had no effect on the plasma membrane Ca2+-ATPase (PMCA) activity in the pharmacological isolated neutrophil preparation and the neutrophil membrane fractions. These results indicate that PAO stimulates [Ca2+]i rise in rat neutrophils mainly through the oxidation of vicinal thiol groups on the cell surface membrane to activation of a non-store operated Ca2+ entry (non-SOCE) without affecting the activity of PMCA and the plasmalemmal Na+/Ca2+ exchanger.

Animals↗
PubMed2001

Highly enantioselective Rh-catalyzed hydrogenation based on phosphine-phosphite ligands derived from carbohydrates.

A new class of efficient catalysts was developed for the asymmetric hydrogenation of alpha,beta-unsaturated carboxylic acid derivatives by synthesizing a series of novel phosphine-phosphite ligands (4a-d) derived from readily available D-(+)-xylose. Excellent enantioselectivities (> 99%) were achieved under very mild reaction conditions (1 bar H(2) and 20 degrees C). Varying the biphenyl substituents in the phosphite moiety greatly affected the enantioselectivity in the hydrogenation reactions. The results also indicate that the sense of enantioselectivity is mainly controlled by the configuration of the phosphite moiety. (31)P[(1)H] NMR and kinetic studies on intermediates of the catalytic cycle show that the [Rh(P(1)-P(2))(enamide)]BF(4) species is the resting state and that the rate dependence is first order in rhodium and hydrogen pressure and zero order in enamide concentration.

Carbohydrates↗
PubMed1994

Phosphinic peptide analogues as potent inhibitors of Corynebacterium rathayii bacterial collagenase.

Pseudo-substrate analogues of collagenase from Corynebacterium rathayii, in which the scissile peptide bond is replaced by a phosphinic moiety, were synthesized and evaluated as inhibitors of this enzyme. The phosphinic tetrapeptide, Z-Phe-psi(PO2CH2)-Gly-Pro-Nle (1), was found to be a potent inhibitor of collagenase with a Ki value of 8 nM. Increasing the length of the phosphinic-containing inhibitors from tetra- to hepta-peptide size further improves the potency of these compounds. The heptapeptide analogue, Z-Phe-Gly-Pro-Phe-psi(PO2CH2)-Gly-Pro-Nle-OMe, with a Ki value of 0.6 nM, is the most potent inhibitor reported to date for bacterial collagenases. A comparison between the phosphinic analogue Z-Phe-psi(PO2CH2)-Gly-Pro-Nle (1) and the phosphonamide peptide Z-Phe-psi(PO2NH)-Gly-Pro-Nle (2) shows that for bacterial collagenase the replacement of a CH2 by an NH group results only in a modest increase in affinity from Ki = 8 nM for compound 1 to Ki = 6 nM for compound 2. Most of the phosphorus-containing inhibitors of this series are slow- or slow-tight-binding inhibitors with second-order rate constants for association and dissociation varying respectively for the kon values from 1 x 10(3) to 26 x 10(3) M-1.s-1 and for the koff values from 3 x 10(-4) to 2 x 10(-5) s-1. Interestingly, the lower affinity of the molecule containing a D residue in the P1 position of the inhibitor, compared with the molecule with an L residue in this position, is mainly the consequence of a lower rate constant for association of these D stereoisomers with the enzyme. This study demonstrates that phosphinic peptide analogues are potent inhibitors of a bacterial collagenase. The development of new phosphinic peptides should lead to the discovery of potent inhibitors of other zinc metalloproteases. Details of how the analogues were synthesized are given in Supplementary Publication SUP 50176 (14 pages), which has been deposited with the British Library Document Supply Centre, Boston Spa, Wetherby, W. Yorkshire LS23 7BQ, from whom copies can be obtained on the terms indicated in Biochem. J. (1994) 297, 9.

Amino Acid Sequence↗
PubMed2004

Solid-phase synthesis of chiral 3,4-diazaphospholanes and their application to catalytic asymmetric allylic alkylation.

Functionalized chiral diazaphospholanes ligate to a variety of transition metals, yielding chiral, catalytically active, metal complexes. Previous work has established that amino acid derivatization of the carboxyl groups of (R,R)-N,N'-phthaloyl-2,3-(2-carboxyphenyl)-phenyl-3,4-diazaphospholane (1) yields phosphines that are excellent ligands for palladium-catalyzed asymmetric allylic alkylation reactions. Alanine functionalization is particularly effective for allylic alkylation of 1,3-dimethylallyl acetate. Standard Merrifield resins and amino acid coupling methods are used to synthesize the bead-attached phosphine having the topology bead-linker-LAla-(R,R)-1-LAla-OMe, as a 1:1 mixture of linkage isomers. Use of this supported phosphine in Pd-catalyzed asymmetric allylic alkylation yields 92% enantiomeric excess, matching prior solution-phase results. A 20-member collection of amino acid-functionalized phosphines on beads with the topology bead-linker-AA(2)-AA(1)-1-AA(1)-AA(2) was synthesized by using parallel solid-state methods and screened for efficacy in allylic alkylation. Resulting enantioselectivities indicate that the AA(1) position has the strongest effect on the reaction. Catalyst activities can vary widely with the nature of the phosphine ligand and the reaction conditions. Meaningful analysis of intrinsic catalytic activities awaits identification of the structure and abundance of the active catalyst.

Alkylation↗
PubMed1987

A comparison of some effects of phosphine, hydrogen cyanide and anoxia in the lesser grain borer, Rhyzopertha dominica (F.) (Coleoptera: Bostrychidae).

The effects of phosphine, hydrogen cyanide and anoxia on levels of ATP, pyruvate and lactate in Rhyzopertha dominica are compared. The effect of phosphine on anaerobiosis is not directly comparable either with HCN or anoxia. Reduction of catalase by feeding 3 amino 1,2,4 triazole does not enhance the toxicity of phosphine in treated insects.

Adenosine Triphosphate↗
PubMed2004

2-Methylene analogs of 1alpha-hydroxy-19-norvitamin D3: synthesis, biological activities and docking to the ligand binding domain of the rat vitamin D receptor.

In continuing efforts towards the synthesis of biologically active vitamin D compounds of potential therapeutic value, new 2-methylene-1alpha-hydroxy-19-norvitamin D(3) analogs 3 and 4 with modified alkyl side chains have been synthesized. The key synthetic step involved Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann type ketones 9, possessing different 17beta-alkyl substituents, with the phosphine oxide 10 prepared from (-)-quinic acid. The prepared vitamins 3 and 4 were ca. eight times less potent than 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) (1) in binding to the rat intestinal vitamin D receptor (VDR). In comparison with the hormone 1 they exhibited slightly lower cellular HL-60 differentiation activity. When tested in vivo; the analog 3 was characterized by very high bone calcium mobilizing potency and intestinal calcium transport activity. Unexpectedly, the 25-methyl compound 4 showed marked calcemic activity in both assays. Computational docking of the vitamin 3 into the binding pocket of the rat vitamin D receptor is also reported.

Animals↗