- Short self-assembling peptides with a urea bond: A new type of supramolecular peptide hydrogel materials
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There is an increasing need to develop short self-assembling peptides (SAPs) that can form hydrogels for cell engineering and biomedical applications. In this study, we proposed new short self-assembling peptides with a symmetric structure via a urea bond
- Tsutsumi, Hiroshi,Tanaka, Kunifumi,Chia, Jyh Yea,Mihara, Hisakazu
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- Synthesis and precursor-directed biosynthesis of new hormaomycin analogues
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Several new analogues of hormaomycin (1), a peptide lactone with interesting biological activities, were prepared by total synthesis or by precursor-directed biosynthesis. The new analogues 2a-c, 3a-c, O-MOM-1 and epi-O-MOM-1 as well as the model acyl tri
- Zlatopolskiy, Boris D.,Radzom, Markus,Zeeck, Axel,De Meijere, Armin
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p. 1525 - 1534
(2007/10/03)
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- Design, synthesis, and biological testing of potential heme-coordinating nitric oxide synthase inhibitors
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Based on computer modeling of the active site of nitric oxide synthases (NOS), a series of 10 amidine compounds (9-18) was designed including potential inhibitors that involve the coordination of side-chain functional groups with the iron of the heme cofactor. The most potent and selective compound was the methylthio amidine analogue 9, which was more potent than l-nitroarginine with 185-fold selectivity for inhibition of neuronal NOS over endothelial NOS. It also exhibited time-dependent inhibition, but did not involve the mechanism previously proposed for other amidine inhibitors of NOS. None of the compounds, however, exhibited heme-binding characteristics according to absorption spectroscopy.
- Litzinger, Elizabeth A.,Martasek, Pavel,Roman, Linda J.,Silverman, Richard B.
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p. 3185 - 3198
(2007/10/03)
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- An expeditious synthesis of pentosidine, an advanced glycation end product
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The chemical synthesis of pentosidine (1), an advanced glycation end product, was achieved via the asymmetric alkylation of the chiral schiff base derived from (+)-2-hydroxy-3-pinanone ((+)-HyPN) and glycine tert-butyl ester, the mercury salt mediated intramolecular guanylation, and the regioselective alkylation of imidazo[4,5-b]pyridine ring. This reliable synthetic achievement will promise availability of pentosidine (1) in quantities.
- Yokokawa, Fumiaki,Sugiyama, Hideyuki,Shioiri, Takayuki,Katagiri, Noriko,Oda, Osamu,Ogawa, Hiroshi
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p. 4759 - 4766
(2007/10/03)
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- Examination of N-hydroxylation as a prerequisite mechanism of nitric oxide synthase inactivation
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L-N5-(1-Hydroxyiminoethyl)-ornithine (L-NHIO) and L-N6-(1-hydroxyiminoethyl)-lysine (L-NHIL) were synthesized and tested as potential intermediates in the mechanism-based inactivation of nitric oxide synthase (NOS) by L-N5-iminoethyl-ornithine (L-NIO) and L-N6-iminoethyllysine (L-NIL). Although these compounds were determined to be competitive inhibitors, mechanism-based inactivation was not observed. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Maurer, Tristan S.,Pan, Jianping,Booth, Brian P.,Kalman, Thomas I.,Fung, Ho-Leung
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p. 1077 - 1080
(2007/10/03)
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- Heterocyclic analogues of L-citrulline as inhibitors of the isoforms of nitric oxide synthase (NOS) and identification of N(δ)-(4,5-dihydrothiazol-2-yl)ornithine as a potent inhibitor
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L-Thiocitrulline is a known potent inhibitor of several isoforms of nitric oxide synthase (NOS). To explore the structure-activity relationships (SARs) for this molecule in more depth than has previously been reported, three analogues substituted at the sulphur of the isothioureas have been synthesised. In two of these, the S-substituent was 'tied back' sterically by cyclisation to the nitrogen remote from the amino-acid unit. N(δ)-(4,5-Dihydrothiazol-2-yl)ornithine was identified as an inhibitor of rat inducible and constitutive isoforms of NOS and of a constitutive NOS derived from a human tumour xenograft. Analogous N(δ)-(thiazol-2-yl)ornithines were less active, whereas the corresponding N(δ)-(oxazol-2-yl)ornithine and N(δ)-(pyrimidin-2-yl)ornithine failed completely to inhibit NOS. A new efficient preparation of the critical synthetic intermediate, N(α)-Boc-thiocitrulline t-butyl ester, has been developed. Further exploration of the SAR with 2-amino-5-(heterocyclylthio)pentanoic acids (synthesised from 2-(Boc-amino)-5-bromopentanoic acid t-butyl ester), with N-(4-aminobutyl)thiourea and with 2-(4-aminobutylamino)-4,5-dihydrothiazole enabled refinement of our previous model for binding of the substrate, L-arginine, and the inhibitors to NOS.
- Ulhaq, Saraj,Chinje, Edwin C.,Naylor, Matthew A.,Jaffar, Mohammed,Stratford, Ian J.,Threadgill, Michael D.
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p. 1787 - 1796
(2007/10/03)
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- Mechanistic studies of the inactivation of inducible nitric oxide synthase by N5-(1-iminoethyl)-L-ornithine (L-NIO)
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Nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to L- citrulline and nitric oxide. N5-(1-iminoethyl)-L-ornithine (L-NIO, 5) is a natural product known to inactivate NOS, but the mechanism of inactivation is unknown. Upon incubation of iNOS with L-NIO a type I binding difference spectrum is observed, indicating that binding at the substrate binding site occurs. L-NIO is shown to be a time-dependent, concentration-dependent, and NADPH-dependent irreversible inhibitor of iNOS with K(I) and k(inact) values of 13.7 ± 1.6 μM and 0.073 ± 0.003 min-1, respectively. During inactivation the heme chromophore is partially lost (Figure 1); HPLC shows that the loss corresponds to about 50% of the heine. Inclusion of catalase during incubation does not prevent heine loss. N5-(1-Imino-2-[14C]ethyl)- L-ornithine (11) inactivates iNOS, but upon dialysis or gel filtration, no radioactivity remains bound to the protein or to a cofactor. The only radioactive product detected after enzyme inactivation is N(ω)-hydroxy-L- NIO (12); no C(ω)-hydroxy-L-NIO (13) or N(δ)-acetyl-L-ornithine (14) is observed (Figure 2). The amount of 12 produced during the inactivation process is 7.7 ± 0.2 equiv per inactivation event. Incubations of 12 with iNOS show time-, concentration-, and NADPH-dependent inactivation that is not reversible upon dilution into the assay solution. Incubations that include an excess of L-arginine or with substitution of NADP+ for NADPH result in no significant loss of enzyme activity. The K(I) and k(inact) values for 12 are 830 ± 160 μM and 0.0073 ± 0.0007 min-1, respectively. The magnitude of these kinetic constants (compared with those of 5) suggest that 12 is not an intermediate of L-NIO inactivation of iNOS. Compound 12 also is a substrate for iNOS, exhibiting saturation kinetics with K(m) and k(cat) values of 800 ± 85 μM and 2.22 min-1, respectively; the product is shown to be N(δ)- acetyl-L-ornithine (14) (Figure 3). The k(cat) and k(inact) values for 12 can be compared directly to give a partition ratio (k(cat)/k(inact)) for inactivation of 304; i.e., there are 304 turnovers to give NO per inactivation event. This high partition ratio further supports the notion that 12 is not involved in L-NIO inactivation of iNOS. C(ω)-Hydroxy-L-NIO (13) is not an inactivator of iNOS. These results suggest that L-NIO inactivation occurs after an oxidation step (NADPH is required for inactivation) but prior to a hydroxylation step (12 and 13 are not involved). Inactivation of iNOS by N5-(1-imino-2-[2H3]-ethyl)-L-ornithine (15) exhibits 3 kinetic isotope effect (H)k(inact)/(D)k(inact) of 1.35 ± 0.08 and on (H)(k(inact)/k(I)/(D)-(k(inact)/K(I) of 1.51 ± 0.3, suggesting that the methyl C-H bond is cleaved in a partially rate-determining step prior to hydroxylation, and that leads to inactivation. A new NADPH-dependent 400 nm peak in the HPLC of L-NIO-inactivated iNOS is produced (Figure 4). LC- electrospray mass spectrometry (Figure 5) demonstrates the m/z of the new metabolite to be 583, which is shown to correspond to biliverdin (23) (Figures 6 and 7). Two possible mechanisms for the formation of biliverdin during inactivation are proposed (Schemes 10 and 11). When 14 is incubated with iNOS, time-, concentration-, and NADPH-dependent loss of enzyme activity is observed (K(I) and k(inact) values are 490 mM and 0.24 min-1, respectively); iNOS inactivation by 14 can be prevented by inclusion of L- arginine, but not D-arginine, in the inactivation mixtures, suggesting that the inactivator acts at the arginine binding site. However, 14 is not produced from L-NIO (Figure 2) and, therefore, is not involved in L-NIO inactivation.
- Fast, Walter,Nikolic, Dejan,Van Breemen, Richard B.,Silverman, Richard B.
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p. 903 - 916
(2007/10/03)
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- Efficient total synthesis of pentosidine, an advanced glycation endproduct
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The efficient total synthesis of pentosidine (1), an advanced glycation endproduct, was achieved using the asymmetric alkylation of a chiral schiff base (2), the intramolecular guanylation with mercury (II) chloride, and the quaternization accompanied by removal of the trityl group as key steps.
- Sugiyama, Hideyuki,Yokokawa, Fumiaki,Shioiri, Takayuki,Katagiri, Noriko,Oda, Osamu,Ogawa, Hiroshi
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p. 2569 - 2572
(2007/10/03)
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- α-Functionalized phosphonylphosphinates: Synthesis and evaluation as transcarbamoylase inhibitors
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Diverse α-methyl-substituted phosphonylphosphinates (P-C-P-C-X) are accessible from a protected, pentafluorophenylsulfonated phosphonylphosphinate via nucleophilic displacement. The utility of this route is demonstrated with several nitrogen nucleophiles. The resulting amine and amino acid phosphonylphosphinate derivatives were evaluated as inhibitors of Streptococcus faecalis ornithine transcarbamoylase (OTC). Compared with the structurally related phosphonoacetyl-L-ornithine (L-PALO), a known inhibitor of OTCs from various sources, the phosphonylphosphinates are surprisingly poor inhibitors, binding several orders of magnitude less tightly to the enzyme. These results suggest that the tetrahedral intermediate formed in the normal transcarbamoylase reaction is poorly mimicked by a tetrahedral and anionic phosphonate, either because of directly unfavorable interactions with a hydrogen-bond acceptor within the active site or because transition-state analogues are unable to induce the protein conformation changes that normally accompany reaction.
- Flohr, Alexander,Aemissegger, Andreas,Hilvert, Donald
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p. 2633 - 2640
(2007/10/03)
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- Synthesis and evaluation of new sulfur-containing L-arginine-derived inhibitors of nitric oxide synthase
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A series of compounds (7, 8, 10-17, 23) containing new functional groups derived by the combination of the substrate, intermediate, product, and known inhibitors of nitric oxide synthase (NOS) were prepared and evaluated against NOS. While none of the com
- Ichimori, Kohji,Stuehr, Dennis J.,Atkinson, Robert N.,King, S. Bruce
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p. 1842 - 1848
(2007/10/03)
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- Heme binding compounds and use thereof
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Inhibitors of nitric oxide formation from arginine useful for treating hypotension, inflammation, stroke and to restore vascular contractile sensitivity to the effects of α1 adrenergic agonists are physiologically active compounds including Ns
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- Synthesis and Biological Activity of the Novel Nitric Oxide Synthase Inhibitor Nω'-Hydroxy-Nω-methyl-L-arginine
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Nω'-Hydroxy-Nω-methyl-L-arginine has been sythesised in eight steps from N5-(benzyloxycarbonyl)-L-ornithine and has been found to inhibit the biosynthesis of nitric oxide.
- Moynihan, Humphrey A.,Roberts, Stanley M.,Weldon, Hazel,Allcock, Graham H.,Aenggard, Erik E.,Warner, Timothy D.
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p. 769 - 772
(2007/10/02)
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- Synthesis of 15N omega-hydroxy-L-arginine and ESR and 15N-NMR studies for the elucidation of the molecular mechanism of enzymic nitric oxide formation from L-arginine.
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N omega-Hydroxy-L-arginine (2) was prepared by a multi-stage synthesis; the key step was the addition of hydroxylamine to the protected cyanamide 8. The presence of N-hydroxyguanidines was confirmed, above all, by 15N-NMR investigations. 15N omega-Hydroxy
- Clement,Schnoerwangen,Kaempchen,Mordvintcev,Muelsch
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p. 793 - 798
(2007/10/02)
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- S-alkyl-isothioureido-amino acids and use thereof
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Inhibitors of nitric oxide formation from arginine useful for treating hypotension, inflammation, stroke and to restore vascular contractile sensitivity to the effects of α1 -adrenergic agonists are physiologically active compounds including Nδ -substituted ornithine or Nε -substituted lysine moieties or monoalkyl carbon-substituted Nδ -substituted ornithine or Nε -substituted lysine moieties, having the formula STR1 wherein R is (CH2)y CH3 or H, R' is CH2 or C(H)(CH2)y CH3, and R" is CH2 or C(H)(CH2)y CH3, with y ranging from 0 to 5, and x is 0 or 1 and wherein none or only one of R, R' and R" provides an alkyl substituent on ornithine or lysine moiety, and wherein Q is alkyl having 1 to 5 carbon atoms, and physiologically acceptable acid addition salts thereof.
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- Methodology for the Preparation of N-Guanidino-Modified Arginines and Related Derivatives
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Methods for the preparation of NG-modified arginines and Nδ-heterocyclic ornithines are described.The reactive cyanamide intermediate tert-butyl Nα-Boc-Nδ-cyano-L-ornithinate (2), prepared either by treatment of
- Wagenaar, Frank L.,Kerwin, James F.
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p. 4331 - 4338
(2007/10/02)
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