The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
Christopher J. Schofield - One of the best experts on this subject based on the ideXlab platform.
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Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins
Nature Chemical Biology, 2007Co-Authors: Pauline Macheboeuf, Andréa Dessen, Delphine S. Fischer, Astrid Zervosen, Bernard Joris, Tom Brown, Andre Luxen, Christopher J. SchofieldAbstract:Beta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance mechanisms that, in Gram-positive bacteria, include mutations to PBPs that enable them to avoid beta-lactam inhibition. Lactivicin (LTV; 1) contains separate cycloserine and gamma-lactone rings and is the only known natural PBP inhibitor that does not contain a beta-lactam. Here we show that LTV and a more potent analog, phenoxyacetyl-LTV (PLTV; 2), are active against clinically isolated, penicillin-resistant Streptococcus pneumoniae strains. Crystallographic analyses of S. pneumoniae PBP1b reveal that LTV and PLTV inhibition involves opening of both monocyclic cycloserine and gamma-lactone rings. In PBP1b complexes, the ring-derived atoms from LTV and PLTV show a notable structural convergence with those derived from a complexed cephalosporin (cefotaxime; 3). The structures imply that derivatives of LTV will be useful in the search for new antibiotics with activity against beta-lactam-resistant bacteria.
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'Ph-Jump' Crystallographic Analyses of Gamma-Lactam-Porcine Pancreatic Elastase Complexes
Biochemical Journal, 2000Co-Authors: P A Wright, R C Wilmouth, I J Clifton, Christopher J. SchofieldAbstract:β-Lactams inhibit a range of enzymes via acylation of nucleophilic serine residues. Certain γ-lactam analogues of monocyclic β-lactams have also been shown to be reversible inhibitors of porcine pancreatic elastase (PPE), forming acyl-enzyme complexes that are stable with respect to hydrolysis. Crystallographic analysis at pH 5 of an acyl-enzyme complex formed with PPE and one of these inhibitors revealed the ester carbonyl located in the oxyanion hole in a similar conformation to that observed in the structure of a complex formed between a heptapeptide (β-casomorphin-7) and PPE. Only weak electron density was observed for the His-57 side chain in its ‘native’conformation. Instead, the His-57 side chain predominantly adopted a conformation rotated approx. 90° from its normal position. PPE–γ-lactam crystals were subjected to ‘pH-jumps’by placing the crystals in a buffer of increased pH prior to freezing for data collection. The results indicate that the conformation of the γ-lactam-derived acyl-enzyme species in the PPE active site is dependent on pH, a result having implications for the analysis of other serine protease–inhibitor structures at non-catalytic pH values. The results help to define the stereoelectronic relationship between the ester of the acyl-enzyme complex, the side chain of His-57 and the incoming nucleophile during the reversible (de)acylation steps, implying it is closely analogous to the hydrolytic deacylation step during catalytic peptide hydrolysis.
John A Rudd - One of the best experts on this subject based on the ideXlab platform.
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Contractile effect of tachykinins on Suncus murinus (house musk shrew) isolated ileum
Neuropeptides, 2008Co-Authors: Frankie H M Cheng, Sze Wa Chan, John A RuddAbstract:Abstract Recent studies used Suncus murinus to investigate the anti-emetic potential of NK 1 tachykinin receptor antagonists. However, the pharmacology of tachykinin receptors in this species has not been fully characterized. In the present studies, therefore, we examined a range of tachykinin receptor agonists for a capacity to induce contractions of the isolated ileum. The tachykinin NK 1 receptor preferring agonists substance P, septide and [Sar 9 Met(O 2 ) 11 ] substance P, and the tachykinin NK 2 preferring agonists neurokinin A and GR 64349 (Lys-Asp-Ser-Phe-Val-Gly-R-Gamma-Lactam-Leu-Met-NH 2 ) caused concentration dependent contractions with EC 50 values in the nanomolar range. However, the tachykinin NK 3 preferring agonists neurokinin B and senktide (1 nM–1 μM) induced only weak contractions. The action of senktide, but not [Sar 9 Met(O 2 ) 11 ] substance P, septide, or GR 64349, was antagonized significantly by atropine ( P 1 receptor antagonist CP-99,994 ((+)-[(2 S ,3 S )-3-(2-methoxy-benzyl-amino)-2-phenylpiperidine]) (10–100 nM) inhibited substance P- and septide-induced contractions non-competitively. The pA 2 value estimated for CP-99,994 against septide was 7.3 ± 0.1. It also non-competitively antagonized the contractile responses induced by [Sar 9 Met(O 2 ) 11 ] substance P with a pA 2 of 7.4 ± 0.1. CP-99,994 also had a slight inhibitory action on neurokinin A-induced contractions, but did not modify the action of GR 64349. Conversely, the tachykinin NK 2 receptor antagonist, saredutant, competitively antagonized GR 64349-induced contractions with a pA 2 of 7.34 ± 0.02. On the other hand, the presence of both CP-99,994 and saredutant competitively antagonized substance P-induced contraction. The present studies indicate that tachykininNK 1 and NK 2 receptors exist in the ileum of S. murinus and are involved in mediating contractions directly on smooth muscle, whereas tachykinin NK 3 receptors may play a minor role involving a release of acetylcholine.
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Contractile effect of tachykinins on Suncus murinus (house musk shrew) isolated ileum.
Neuropeptides, 2008Co-Authors: Frankie H M Cheng, Sze Wa Chan, John A RuddAbstract:Recent studies used Suncus murinus to investigate the anti-emetic potential of NK(1) tachykinin receptor antagonists. However, the pharmacology of tachykinin receptors in this species has not been fully characterized. In the present studies, therefore, we examined a range of tachykinin receptor agonists for a capacity to induce contractions of the isolated ileum. The tachykinin NK1 receptor preferring agonists substance P, septide and [Sar9Met(O2)11] substance P, and the tachykinin NK2 preferring agonists neurokinin A and GR 64349 (Lys-Asp-Ser-Phe-Val-Gly-R-Gamma-Lactam-Leu-Met-NH2) caused concentration dependent contractions with EC50 values in the nanomolar range. However, the tachykinin NK3 preferring agonists neurokinin B and senktide (1nM-1microM) induced only weak contractions. The action of senktide, but not [Sar9Met(O2)11] substance P, septide, or GR 64349, was antagonized significantly by atropine (P
R.g. Da Rosa - One of the best experts on this subject based on the ideXlab platform.
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Rhodium-catalyzed carbonylation of allylaminoalcohols: Catalytic synthesis of N-(2-hydroxy-alkyl)-Gamma-Lactams and bicyclic oxazolidines
Journal of Molecular Catalysis A: Chemical, 2020Co-Authors: J. Limberger, M. Mottin, F.f. Nachtigall, E.e. Castellano, R.g. Da RosaAbstract:Gamma-Lactams and bicyclic oxazolidines are important structural frameworks in both synthetic organic chemistry and related pharmacological fields. These heterocycles can be prepared by the rhodium-catalyzed carbonylation of unsaturated amines. In this work, allylaminoalcohols, derived from the aminolysis of cyclohexene oxide, styrene oxide, (R)-(+)-limonene oxide, and ethyl-3-phenyl-glicidate, were employed as substrates. These allylaminoalcohols were carbonylated by employing RhClCO(PPh3)(2) as a precatalyst under varying CO/H-2 mixtures, and moderate to excellent yields were obtained, depending on the substrate used. The results indicated that an increase in the chelating ability of the substrate (-OH and -NHR moieties) decreased the conversion and selectivity of the ensuing reaction. Additionally, the selectivity could be optimized to favor either the Gamma-Lactams or the oxazolidines by controlling the CO/H-2 ratio. A large excess of CO provided a lactam selectivity of up to 90%, while a H-2-rich gas mixture improved the selectivity for oxazolidines, resulting from hydroformylation/cyclization. Studies of the reaction temperature indicated that an undesirable substrate deallylation reaction occurs at higher temperature (>100 degrees C). Further, kinetic studies have indicated that the oxazolidines and Gamma-Lactams were formed through parallel routes. Unfortunately, the mechanism for oxazolidines formation is not yet well understood. However, our results have led us to propose a catalytic cycle based on hydroformylation/acetalyzation pathways. The Gamma-Lactams formation follows a carbonylation route, mediated by a rhodium-carbamoylic intermediate, as previously reported. To this end, we have been able to prepare and isolate the corresponding iridium complex, which could be confirmed by X-ray crystallographic analysis. (C) 2008 Elsevier B.V. All rights reserved.CAPESCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES
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Rhodium-catalyzed carbonylation of allylaminoalcohols : Catalytic synthesis of N-(2-hydroxy-alkyl)-Gamma-Lactams and bicyclic oxazolidines
Journal of Molecular Catalysis A-chemical, 2008Co-Authors: J. Limberger, M. Mottin, F.f. Nachtigall, E.e. Castellano, R.g. Da RosaAbstract:Abstract Gamma-Lactams and bicyclic oxazolidines are important structural frameworks in both synthetic organic chemistry and related pharmacological fields. These heterocycles can be prepared by the rhodium-catalyzed carbonylation of unsaturated amines. In this work, allylaminoalcohols, derived from the aminolysis of cyclohexene oxide, styrene oxide, ( R )-(+)-limonene oxide, and ethyl-3-phenyl-glicidate, were employed as substrates. These allylaminoalcohols were carbonylated by employing RhClCO(PPh 3 ) 2 as a precatalyst under varying CO/H 2 mixtures, and moderate to excellent yields were obtained, depending on the substrate used. The results indicated that an increase in the chelating ability of the substrate (–OH and –NHR moieties) decreased the conversion and selectivity of the ensuing reaction. Additionally, the selectivity could be optimized to favor either the γ-lactams or the oxazolidines by controlling the CO/H 2 ratio. A large excess of CO provided a lactam selectivity of up to 90%, while a H 2 -rich gas mixture improved the selectivity for oxazolidines, resulting from hydroformylation/cyclization. Studies of the reaction temperature indicated that an undesirable substrate deallylation reaction occurs at higher temperature (>100 °C). Further, kinetic studies have indicated that the oxazolidines and γ-lactams were formed through parallel routes. Unfortunately, the mechanism for oxazolidines formation is not yet well understood. However, our results have led us to propose a catalytic cycle based on hydroformylation/acetalyzation pathways. The γ-lactams formation follows a carbonylation route, mediated by a rhodium–carbamoylic intermediate, as previously reported. To this end, we have been able to prepare and isolate the corresponding iridium complex, which could be confirmed by X-ray crystallographic analysis.
Rodney L. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Crystal‐state structural analysis of two γ‐lactam‐restricted analogs of Pro‐Leu‐Gly‐NH2
International Journal of Peptide and Protein Research, 2009Co-Authors: Giovanni Valle, Marco Crisma, Claudio Toniolo, K.-l. Yu, Rodney L. JohnsonAbstract:Abstract The crystal structures of two analogs of Pro-Leu-Gly-NH2 (1), containing a Gamma-Lactam conformational constraint in place of the -Leu-Gly- sequences, are described. The highly biologically active (S,R)-diastereomer 2a is semi-extended at the C-terminus, with the N-terminal Pro residue in the unusual "C5" conformation [psi 1 = -0.8(15) degrees] stabilized by a (peptide)N-H...N(amino) intramolecular H-bond [the N(3)...N(4) separation is 2.687(11)A]. Conversely, the N,N'-isopropylidene aminal trihydrate of the (S,S)-diastereomer 2b, compound 3, adopts a beta-bend conformation at the C-terminus, as already reported for 1. However, the backbone torsion angles [phi 2 = 57.4(4), psi 2 = -129.9(3) degrees; psi 3 = -92.3(4), phi 3 = 6.4(5) degrees] lie close to the values expected for the corner residues of an ideal type-II' beta-bend. A weak intramolecular 4----1 H-bond is seen between the Gly carboxyamide anti-NH and Pro C = O groups. In the newly formed 2,2,3,4-tetraalkyl-5-oxo-imidazolidin-1-yl moiety the psi 1 torsion angle is 12.9(4) degrees and the intramolecular N(3)...N(4) separation is 2.321(4)A.
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Synthesis and Dopamine Receptor Modulating Activity of Lactam Conformationally Constrained Analogues of Pro-Leu-Gly-NH2
Journal of Medicinal Chemistry, 1993Co-Authors: Uma Sreenivasan, Ram K. Mishra, Rodney L. JohnsonAbstract:A series of analogues of the potent analogue of Pro-Leu-Gly-NH2 (PLG), 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacet amide (2) were synthesized in which the (R)-Gamma-Lactam residue of 2 was replaced with a (R)-beta-lactam, (R)-aminosuccinimide, (R)-cycloseryl, (R)-delta-lactam, (R)-epsilon-lactam, or (S)-epsilon-lactam residue to give analogues 3-8, respectively. These substitutions were made so as to vary the psi 2 torsion angle. The analogues were tested for their ability to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor. Analogues 3-6 and 8 exhibited dose-response curves that were bell-shaped in nature with the maximum effect occurring at a concentration of 1 microM. Analogue 7 was inactive. Analogues 3 and 4 were found to be as effective as PLG, while analogues 5, 6, and 8 appeared to be more effective than PLG in terms of enhancing the binding of ADTN to dopamine receptors. The activity of analogues 3-6 and 8 with their psi 2 angles in the vicinity of that observed in a type II beta-turn is consistent with the hypothesis that this type of turn is the bioactive conformation of PLG.
P A Wright - One of the best experts on this subject based on the ideXlab platform.
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'pH-jump' crystallographic analyses of Gamma-Lactam-porcine pancreatic elastase complexes.
The Biochemical journal, 2000Co-Authors: P A Wright, R C Wilmouth, I J Clifton, C J SchofieldAbstract:beta-Lactams inhibit a range of enzymes via acylation of nucleophilic serine residues. Certain Gamma-Lactam analogues of monocyclic beta-lactams have also been shown to be reversible inhibitors of porcine pancreatic elastase (PPE), forming acyl-enzyme complexes that are stable with respect to hydrolysis. Crystallographic analysis at pH 5 of an acyl-enzyme complex formed with PPE and one of these inhibitors revealed the ester carbonyl located in the oxyanion hole in a similar conformation to that observed in the structure of a complex formed between a heptapeptide (beta-casomorphin-7) and PPE. Only weak electron density was observed for the His-57 side chain in its 'native' conformation. Instead, the His-57 side chain predominantly adopted a conformation rotated approx. 90 degrees from its normal position. PPE-Gamma-Lactam crystals were subjected to 'pH-jumps' by placing the crystals in a buffer of increased pH prior to freezing for data collection. The results indicate that the conformation of the Gamma-Lactam-derived acyl-enzyme species in the PPE active site is dependent on pH, a result having implications for the analysis of other serine protease-inhibitor structures at non-catalytic pH values. The results help to define the stereoelectronic relationship between the ester of the acyl-enzyme complex, the side chain of His-57 and the incoming nucleophile during the reversible (de)acylation steps, implying it is closely analogous to the hydrolytic deacylation step during catalytic peptide hydrolysis.
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'Ph-Jump' Crystallographic Analyses of Gamma-Lactam-Porcine Pancreatic Elastase Complexes
Biochemical Journal, 2000Co-Authors: P A Wright, R C Wilmouth, I J Clifton, Christopher J. SchofieldAbstract:β-Lactams inhibit a range of enzymes via acylation of nucleophilic serine residues. Certain γ-lactam analogues of monocyclic β-lactams have also been shown to be reversible inhibitors of porcine pancreatic elastase (PPE), forming acyl-enzyme complexes that are stable with respect to hydrolysis. Crystallographic analysis at pH 5 of an acyl-enzyme complex formed with PPE and one of these inhibitors revealed the ester carbonyl located in the oxyanion hole in a similar conformation to that observed in the structure of a complex formed between a heptapeptide (β-casomorphin-7) and PPE. Only weak electron density was observed for the His-57 side chain in its ‘native’conformation. Instead, the His-57 side chain predominantly adopted a conformation rotated approx. 90° from its normal position. PPE–γ-lactam crystals were subjected to ‘pH-jumps’by placing the crystals in a buffer of increased pH prior to freezing for data collection. The results indicate that the conformation of the γ-lactam-derived acyl-enzyme species in the PPE active site is dependent on pH, a result having implications for the analysis of other serine protease–inhibitor structures at non-catalytic pH values. The results help to define the stereoelectronic relationship between the ester of the acyl-enzyme complex, the side chain of His-57 and the incoming nucleophile during the reversible (de)acylation steps, implying it is closely analogous to the hydrolytic deacylation step during catalytic peptide hydrolysis.
