- Nickel(III) oxidation of its glycylglycylhistamine complex
-
The doubly-deprotonated Ni(III) complex of Gly2Ha (where Ha is histamine) undergoes base-assisted oxidative self-decomposition of the peptide. At ≤ p[H+] 7.0, a major pathway is a two-electron oxidation at the a-carbon of the N-terminal glycyl residue. Major products (up to 73%) of this two-electron oxidation are glyoxylglycylhistamine and ammonia. Glyoxylglycylhistamine will decay to give isocyanatoacetylhistamine and formaldehyde. Two-electron oxidations of the second glycyl and histamine residues occur as minor pathways (12% of the total possible reaction). Above p[H+] 8.5, two Ni(III)-peptide complexes form an oxo bridge in the axial positions to give a reactive dimer species. This proximity allows the resulting Ni(III)-peptide radical intermediates to undergo peptide-peptide cross-linking at the N-terminal glycyl residues. The products found below p[H+] 7.0 are observed above p[H+] 8.5 as well, although in lower yields. In contrast to this work, NiIII(H- 2Gly2HisGly) undergoes a four-electron oxidation at the N-terminal glycyl residue. Oxidation at the internal glycyl and histidyl residues are not observed. The reactivity of NiIII(H -2Gly2Ha)+ is also different than Cu III(H-2Gly2Ha)+, which undergoes a two-electron oxidation at the histamine group with no peptide-peptide cross-linking in basic solution.
- Green, Brandon J.,Tesfai, Teweldemedhin M.,Margerum, Dale W.
-
-
Read Online
- Conformational preference of glycinamide in solution: An answer derived from combined experimental and computational studies
-
Conformational problems are often subtle but very important in controlling many intricate features in chemistry and biochemistry. We have performed the conformational analysis of glycinamide using NMR experiments and computational studies. 1H NMR experiments suggest the prevalence of intramolecular hydrogen bonded conformation of glycinamide (2B) in acetonitrile, whereas, non-intramolecular hydrogen bonded conformation 2A is favoured in dimethylsulfoxide. The NOESY experiments carried out for glycinamide in DMSO-d6, showed stronger NOE interaction of the NHa-atom of amide group with CH2 than that of NHb-atom confirming the presence of conformer 2A. DFT calculations performed with explicit DMSO molecules also suggested a clear preference for the conformer 2A. The molecular dynamics simulations performed with the explicit DMSO molecules also showed that the intermolecular hydrogen bonding exists between the solvent and solute molecules to stabilize the conformer 2A. The present study sheds light on the debate of conformational preference of neutral glycinamide in the present literature.
- Ganguly, Bishwajit,Kesharwani, Manoj K.,Basari?, Nikola,Suresh, Eringathodi,Biswas, Abul Kalam,Mlinari?-Majerski, Kata
-
-
Read Online
- Preparation method of 2, 6-dichloropyrazine
-
The invention discloses a preparation method of 2, 6-dichloropyrazine. The method comprises the following steps: taking glycine and glyoxal as raw materials, carrying out ammoniation and cyclization reactions to prepare 2-hydroxypyrazine sodium; and reacting 2-hydroxypyrazine sodium with thionyl chloride under the catalytic action of N,N-diisopropylethylamine to prepare 2-chloropyrazine; wherein pyridine is used as a solvent, and 2-chloropyrazine is subjected to chlorination of chlorine to obtain 2,6-dichloropyrazine. The method has the advantages that the raw material namely glycine is cheapand easily available, and phosphorus oxychloride is not used as a chlorination reagent, so that the generation of organic phosphorus-containing wastewater is greatly reduced, and an effective way is provided for efficient green industrial production of 2, 6-dichloropyrazine.
- -
-
Paragraph 0034-0035
(2020/04/22)
-
- Corresponding amine nitrile and method of manufacturing thereof
-
The invention relates to a manufacturing method of nitrile. Compared with the prior art, the manufacturing method has the characteristics of significantly reduced using amount of an ammonia source, low environmental pressure, low energy consumption, low production cost, high purity and yield of a nitrile product and the like, and nitrile with a more complex structure can be obtained. The invention also relates to a method for manufacturing corresponding amine from nitrile.
- -
-
Paragraph 0138; 0139; 0140; 0145; 0146
(2018/05/07)
-
- HEMIAMINAL-TAG FOR PROTEIN LABELING AND PURIFICATION
-
The invention pertains to the synthesis, isolation, and characterization of hemiaminal for selective labeling of peptides, proteins, antibodies, and organic fragments with -C(=0) CH2NH2 and derivatives with -CH2NH2 group over -C(=0) CHRNH2 group (where R≠H). The invention also pertains to the method of single-site immobilization of proteins through N-terminus Gly on solid phase. The invention includes late-stage tagging of N-terminus Gly with an affinity tag, 19F NMR probe, and a fluorophore and a method for metal-free protein purification and isolation of analytically pure proteins.
- -
-
Page/Page column 22
(2018/06/30)
-
- Superactivity of MOF-808 toward Peptide Bond Hydrolysis
-
MOF-808, a Zr(IV)-based metal-organic framework, has been proven to be a very effective heterogeneous catalyst for the hydrolysis of the peptide bond in a wide range of peptides and in hen egg white lysozyme protein. The kinetic experiments with a series of Gly-X dipeptides with varying nature of amino acid side chain have shown that MOF-808 exhibits selectivity depending on the size and chemical nature of the X side chain. Dipeptides with smaller or hydrophilic residues were hydrolyzed faster than those with bulky and hydrophobic residues that lack electron rich functionalities which could engage in favorable intermolecular interactions with the btc linkers. Detailed kinetic studies performed by 1H NMR spectroscopy revealed that the rate of glycylglycine (Gly-Gly) hydrolysis at pD 7.4 and 60 °C was 2.69 × 10-4 s-1 (t1/2 = 0.72 h), which is more than 4 orders of magnitude faster compared to the uncatalyzed reaction. Importantly, MOF-808 can be recycled several times without significantly compromising the catalytic activity. A detailed quantum-chemical study combined with experimental data allowed to unravel the role of the {Zr6O8} core of MOF-808 in accelerating Gly-Gly hydrolysis. A mechanism for the hydrolysis of Gly-Gly by MOF-808 is proposed in which Gly-Gly binds to two Zr(IV) centers of the {Zr6O8} core via the oxygen atom of the amide group and the N-terminus. The activity of MOF-808 was also demonstrated toward the hydrolysis of hen egg white lysozyme, a protein consisting of 129 amino acids. Selective fragmentation of the protein was observed with 55% yield after 25 h under physiological pH.
- Ly, Hong Giang T.,Fu, Guangxia,Kondinski, Aleksandar,Bueken, Bart,De Vos, Dirk,Parac-Vogt, Tatjana N.
-
p. 6325 - 6335
(2018/05/14)
-
- Tuning the reactivity of nitriles using Cu(ii) catalysis-potentially prebiotic activation of nucleotides
-
During the transition from prebiotic chemistry to biology, a period of solution-phase, non-enzymatic activation of (oligo)nucleotides must have occurred, and accordingly, a mechanism for phosphate activation must have existed. Herein, we detail results of an investigation into prebiotic phosphate activation chemistry using simple, prebiotically available nitriles whose reactivity is increased by Cu2+ ions. Furthermore, although Cu2+ ions are known to catalyse the hydrolysis of phosphodiester bonds, we found this deleterious activity to be almost completely suppressed by inclusion of amino acids or dipeptides, which may suggest a productive relationship between protein and RNA from the outset.
- Liu, Ziwei,Mariani, Angelica,Wu, Longfei,Ritson, Dougal,Folli, Andrea,Murphy, Damien,Sutherland, John
-
p. 7053 - 7057
(2018/09/25)
-
- Methanol or formaldehyde ammoxidizing method of synthesizing amide
-
The invention relates to a methanol or formaldehyde ammoxidizing the method of synthesizing amide. Using methanol or formaldehyde, ammonia and air as the raw materials, in 1-3 gas reactor is continuously carried out in a catalytic reaction, synthesis (C-C) is provided with a carbon-carbon single bond or carbon-carbon-carbon single bond amide (C-C-C) organic compound (called C 2 or C 3 amide, mainly hydroxy acetamide, amino acetamide, diglycolamidic amide, malonamide and nitrilo- three b amide).
- -
-
Paragraph 0035; 0038
(2016/10/09)
-
- Chemical evolution of aminoacetonitrile to glycine under discharge onto primitive hydrosphere: Simulation experiments using glow discharge
-
Aminoacetonitrile is an important precursor of abiotic amino acids, as shown in the mechanism that was developed to explain the results of the Miller-type spark-discharge experiment. In present experimental setup, a spark discharge is generated in a simulated reducing atmosphere to yield hydrogen cyanide, aldehyde and ammonia; in a second step, a solution-phase reaction proceeds via aminoacetonitrile to give amino acids. However, when the same experiment is carried out in a non-reducing atmosphere, the yield of amino acids is very low. Contact glow discharge electrolysis onto the aqueous phase, which simulates an energy source for chemical evolution, converted aminoacetonitrile via glycinamide to glycine. The mechanism of glycinamide formation was explained by considering the addition of hydrogen and hydroxyl radicals to the C-N triple bond and subsequent transformation into the amide, which was then oxidized to the amino acid. This research suggests that amino acid amides and amino acids can be obtained through oxidation-reduction with H and OH radicals in the primitive hydrosphere whether under reducing or non-reducing conditions.
- Munegumi
-
p. 555 - 561
(2016/01/20)
-
- Development and evaluation of novel phosphotyrosine mimetic inhibitors targeting the Src homology 2 domain of signaling lymphocytic activation molecule (SLAM) associated protein
-
Specific interactions between Src homology 2 (SH2) domain-containing proteins and the phosphotyrosine-containing counterparts play significant role in cellular protein tyrosine kinase (PTK) signaling pathways. The SH2 domain inhibitors could potentially serve as drug candidates in treating human diseases. Here we have incorporated a novel phosphotyrosine mimetic, which is an unusual amino acid carrying a cyclosaligenyl (cycloSal) phosphodiester moiety, into dipeptides to investigate the inhibitory effect on SH2 domain-containing proteins. A plate-based assay was also established to screen for inhibitors that disrupt the interaction between a phosphopeptide of SLAM (signaling lymphocytic activation molecule) and its interacting protein SAP (SLAM-associated protein). We identified a number of inhibitors with IC50 values in the range of 17-35 μM, implying that the cycloSal phosphodiester-carrying amino acid could mimic the phosphotyrosyl residue. Our results also raise the possibility of integrating the newly developed phosphotyrosine mimetic moiety into inhibitors designed for other SH2 domain-containing proteins.
- Chu, Chi-Yuan,Chang, Chun-Ping,Chou, Yun-Ting,Handoko,Hu, Yi-Ling,Lo, Lee-Chiang,Lin, Jing-Jer
-
p. 2841 - 2849
(2013/06/04)
-
- 2-(N-Benzyl-N-phenylsulfonamido)alkyl amide derivatives as γ-secretase inhibitors
-
A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described.
- Parker, Michael F.,Barten, Donna M.,Bergstrom, Carl P.,Bronson, Joanne J.,Corsa, Jason A.,Dee, Michael F.,Gai, Yonghua,Guss, Valerie L.,Higgins, Mendi A.,Keavy, Daniel J.,Loo, Alice,Mate, Robert A.,Marcin, Larry R.,McElhone, Katharine E.,Polson, Craig T.,Roberts, Susan B.,MacOr, John E.
-
p. 6828 - 6831,4
(2020/09/02)
-
- Efficient N-terminal labeling of proteins by use of sortase
-
"Sorting out" N-terminal labeling: The reversibility of transpeptidase reactions makes protein N-terminal labeling challenging. Depsipeptide substrates for sortase A release alcohol by-products, which are poor nucleophiles for the reverse reaction, during ligation. Proteins with an unhindered N-terminal glycine residue can be labeled efficiently with only a minimal excess of the labeling reagent (see scheme).
- Williamson, Daniel J.,Fascione, Martin A.,Webb, Michael E.,Turnbull, W. Bruce
-
supporting information
p. 9377 - 9380
(2012/11/06)
-
- PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
-
The invention relates to a process for straightening keratin fibres, comprising: (i) a step in which a straightening composition containing at least two denaturing agents is applied to the keratin fibres, (ii) a step in which the temperature of the keratin fibres is raised, using a heating means, to a temperature of between 110 and 250° C.
- -
-
-
- Synthesis of α-amino and α-hydroxy acids under volcanic conditions: implications for the origin of life
-
Facile synthesis of α-hydroxy and α-amino acids is observed at temperatures from 145 to 280 °C with catalytic Ni2+, with cyano ligands as source for C and N, and with CO as a reductant and as a source for C. Implications for the problem of the origin of life are discussed.
- Huber, Claudia,Eisenreich, Wolfgang,W?chtersh?user, Günter
-
scheme or table
p. 1069 - 1071
(2010/04/05)
-
- Convenient synthesis of C-terminal di- and tri-peptide amides from N-protected dipeptidoylbenzotriazoles
-
N-Protected dipeptidoylbenzotriazoles react with aqueous ammonia to give dipeptide primary amides (77-98%) and with N-unprotected α-amino amides to afford tripeptide primary amides (82-86%).
- Celik, Ilhami,Abdel-Fattah, Ashraf A.A.
-
body text
p. 4923 - 4929
(2009/10/09)
-
- Structure-stability correlations for imine formation in aqueous solution
-
Imine formation between 25 aldehydes and 13 amines in aqueous solution in the pH range 7-11 was studied by 1H NMR spectroscopy. A three-parameter linear equation correlating logarithms of imine formation constants with pKa and HOMO energies of amines and LUMO energies of aldehydes is proposed. In view of the widespread occurrence of imine-forming processes in both chemistry and biology, the data presented are of significance for physical organic chemistry and of particular interest for dynamic combinatorial chemistry. Copyright
- Godoy-Alcantar,Yatsimirsky, Anatoly K.,Lehn
-
p. 979 - 985
(2007/10/03)
-
- Peptides having antiangiogenic activity
-
Peptides of formula (I) Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11??(I), are useful for inhibiting angiogenesis. Also disclosed are angiogenesis-inhibiting compositions and methods of inhibiting angiogenesis in a mammal.
- -
-
-
- N-alkylated peptides having antiangiogenic activity
-
N-Alkylated peptides of formula (I) Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11??(I), are useful for inhibiting angiogenesis. Also disclosed are angiogenesis-inhibiting compositions and methods of inhibiting angiogenesis in a mammal.
- -
-
-
- Hypoglycemic imidazoline compounds
-
This invention relates to certain novel imidazoline compounds and analogues thereof, to their use for the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present, to pharmaceutical compositions comprising them, and to processes for their preparation.
- -
-
-
- Compounds having growth hormone releasing activity
-
Compounds that promote growth hormone releasing activity are disclosed. These compounds have the formula: A1-A2-X; A1-X′; or A1.-Y These compounds can be present in a pharmaceutical composition. The compounds can be used with a second compound that acts as an agonist at the growth hormone releasing hormone receptor or which inhibits the effects of somatostatin. These compounds can be used for a variety of uses such as treating hypothalamic pituitary dwarfism, osteoporosis, burns, or promoting wound healing.
- -
-
-
- Isoquinoline derivatives and isoquinoline combinatorial libraries
-
The present invention provides the synthesis of heterocyclic compounds based on the isoquinoline ring. More specifically, the invention provides novel isoquinoline derivatives as well as novel libraries comprised of such compounds.
- -
-
-
- EM2487, a novel anti-HIV-1 antibiotic, produced by Streptomyces sp. Mer-2487: Taxonomy, fermentation, biological properties, isolation and structure elucidation
-
For the purpose of discovering novel agents that inhibit HIV-1 replication at the transcriptional level, we have established cell lines reflecting the HIV-1 long terminal repeat-driven gene expression. Using these cell lines, we have screened approximately 10,000 microorganism products and found that the culture supernatant of Streptomyces sp. Mer-2487 suppresses the HIV-1 Tat-induced gene expression without affecting the basal or tumor necrosis factor-α-induced transcription. The purified active component has a unique structure. This compound has an inhibitory effect on HIV-1 replication in chronically infected cells as well as acutely infected cells, suggesting that the inhibition occurs at a postintegration step of HIV-1 proviral DNA in the HIV-1 replication cycle.
- Takeuchi, Hitoshi,Asai, Naoki,Tanabe, Kazunori,Kozaki, Teruya,Fujita, Masanori,Sakai, Takashi,Okuda, Akifumi,Naruse, Nobuaki,Yamamoto, Satoshi,Sameshima, Tomohiro,Heida, Naohiko,Dobashi, Kazuyuki,Baba, Masanori
-
p. 971 - 982
(2007/10/03)
-
- Isoquinoline derivatives and isoquinoline combinatorial libraries
-
The present invention provides the synthesis of heterocyclic compounds based on the isoquinoline ring. More specifically, the invention provides novel isoquinolines as well as novel libraries comprised of many such compounds, and methods of synthesizing the libraries.
- -
-
-
- ISOQUINOLINE DERIVATIVES AND ISOQUINOLINE COMBINATORIAL LIBRARIES
-
The present invention provides the synthesis of heterocyclic compounds based on the isoquinoline ring. More specifically, the invention provides novel isoquinolines as well as novel libraries comprised of many such compounds, and methods of synthesizing the libraries.
- -
-
-
- Preservation of the Fmoc protective group under alkaline conditions by using CaCl2. Applications in peptide synthesis
-
CaCl2 is shown to dramatically increase the lifetime of the Fmoc protective group in alkaline iPrOH-H2O but has little effect on hydrolytic processes. This enables efficient preparation of Fmoc-protected peptide segments by saponification of the corresponding C-terminal methyl or benzyl esters. Similarly, protected peptide segments prepared by Fmoc/tBu solid- phase synthesis can be selectively released from the support by CaCl2- catalyzed alkaline hydrolysis of an N-acylurea-based linker.
- Pascal, Robert,Sola, Regine
-
p. 5031 - 5034
(2007/10/03)
-
- Substituent effect on acidity of substituted 2-(4-nitrobenzoylamino)alkanamidesin methanol-dimethyl sulfoxide mixtures
-
The dissociation constants of substituted 2-(4-nitrobenzoylamino)alkanamides, N-[2-(4-nitrobenzoylamino)aikanoyl]pyrrolidines, and N-alkyl-4-nitrobenzamides have been measured spectrophotometrically in 60 and 80% v/v DMSO. The pKA values of these N-acids are discussed from the point of view of substituents at the acetamide a-carbon atom.
- Mitas, Petr,Sedlak, Milos,Kavalek, Jaromir
-
-
- INHIBITORS OF TNF-ALPHA SECRETION
-
Compounds and methods are disclosed that are useful in inhibiting the TNF-α converting enzyme (TACE) responsible for cleavage of TNF-. alpha. precursor to provide biologically active TNF-α. The compounds employed in the invention are peptidyl derivatives having active groups capable of inhibiting TACE such as, hydroxamates, thiols, phosphoryls and carboxyls.
- -
-
-
- BENZODIAZEPINE DERIVATIVES, COMPOSITIONS CONTAINING THEM AND THEIR USE IN THERAPY
-
Compounds of Formula (I), and salts and prodrugs thereof wherein: R. sup.1 is H, certain optionally substituted C 1-6 alkyl or C 3-7 cycloalkyl; R 2 represents a group (a) wherein X is O, S or NR 8 where R 8 is H or C 1-4 alkyl; one of Z and Y is C= O and the other is O, S or NR 9, where R 9 is H or C 1-4 alkyl; R 3 is C 1-6 alkyl, halo or NR 6 R 7 ; R 4 is C 3-10 cycloalkyl; n is 0, 1, 2 or 3, and are CCK and/or gastrin antagonists, which compounds and compositions thereof are useful in therapy.
- -
-
-
- Reaction enthalpies for M+L = M+ + L, where M+ = Na+ and K+ and L = acetamide, N-methylacetamide, N,N-dimethylacetamide, glycine, and glycylglycine, from determinations of the collision-induced dissociation thresholds
-
With electrospray (ES), ions present in solution can be transferred to the gas phase. The method provides unique opportunities for studies of hitherto inaccessible ions. Collision-induced dissociation threshold measurements of gas phase ions produced by ES are described. The thresholds for the reactions M+L = M+ + L, where M+ is Na+ or K+ and L is acetone, dimethyl sulfoxide, acetamide, N-methylacetamide, N,N-dimethylacetamide, glycine, glycinamide, succinamide, and glycylglycine, were determined. Enthalpy changes for the reaction were derived from these data.
- Klassen, John S.,Anderson, Stephen G.,Blades, Arthur T.,Kebarle, Paul
-
p. 14218 - 14227
(2007/10/03)
-
- α-Aminonitrile hydration in the presence of hydrogen peroxide in aqueous basic medium
-
α-Aminonitriles are hydrated into α-aminoamides in the presence of hydrogen peroxide in sodic or ammoniacal basic medium. While the hydration mechanism is close to the mechanism described previously in the case of aromatic nitrites, we showed that, in weakly basic conditions, the amine function of α-aminonitrile is competitively oxidized via a peroxyimidic acid by an intramolecular process. In the case of 2-aminopropanenitrile, this reaction leads to pyruvamide oxime. Furthermore, the study of structurereactivity relationships in the hydration of aliphatic and aromatic monofunctional nitriles and α-aminonitriles showed that the reactivity of the substrates towards hydroperoxide onion, which mostly depends on inductive effects of the substituents, is sufficiently enhanced to allow hydration of tertiary α-aminonitriles with low steric hindrance and regioselective hydration of dissymmetric α-aminodinitriles. Eisevier,.
- Taillades, Jacques
-
-
- Benzodiazepine derivatives, compositions containing them and their use in therapy
-
Compounds of formula (I), and salts and prodrugs thereof STR1 wherein: R 1 is H, certain optionally substituted C 1-6 alkyl, or C 3-7 cyclocalkyl;R 2 represents a group STR2 wherein X is O, S or NR 8 where R 8 is H or C 1-4 alkyl; R 3 is C 1-6 alkyl, halo or NR 6 R 7 ;R 4 is C 1-7 alkyl, C 3-7 cycloalkyl, C 4-7 cycloalkylalkyl or optionally substituted aryl;n is 0, 1, 2 or 3; are CCK and/or gastrin receptor antagonists. They and compositions thereof are useful in therapy.
- -
-
-
- Kinetics of reversible carbon deprotonation of 2-nitroethanol and 2-nitro-1,3-propanediol by hydroxide ion, water, amines, and carboxylate ions. A normal br?nsted α despite an imbalanced transition state
-
Rates of reversible carbon deprotonation of 2-nitroethanol (2) and 2-nitro-1,3-propanediol (3) by hydroxide ion, water, amines, and carboxylate ions and pKa values for the ionization at carbon (pKaCH) and oxygen (pKaOH) and ionization of the aci-forms (pKaNOH) were determined in aqueous solution at 25 °C. The pKaCH values for 2 and 3 are 8.60 and 7.68, respectively, as compared to 10.22 for CH3NO2. The acidifying effect of the CH2OH groups is attributed to a combination of inductive electron withdrawal and hyperconjugative stabilization of the respective nitronate ions, possibly coupled with intramolecular hydrogen bonding stabilization of this ion. The higher acidity of 2-nitroethanol compared to nitromethane is reflected in higher rates of proton transfer from 2-nitroethanol, implying a "normal" Br?nsted α between 0 and 1. This contrasts with the negative α value based on the reaction of OH- with nitromethane, nitroethane, and 2-nitropropane (Kresge, A. J. Can. J. Chem. 1974, 52, 1897). Reasons why a normal α value is observed in the current system are discussed.
- Bernasconi, Claude F.,Panda, Markandeswar,Stronach, Michael W.
-
p. 9206 - 9212
(2007/10/03)
-
- Mechanism of inactivation of monoamine oxidase-B by the anticonvulsant agent milacemide (2-(n-pentylamino)acetamide)
-
The anticonvulsant agent milacemide (2-(n-pentylamino)acetamide) is known to inactivate monoamine oxidase-B (MAO-B). Various isotopically labeled analogues of milacemide are used to elucidate the mechanism of inactivation of MAO-B by this compound. The metabolites of the oxidation of milacemide by MAO-B (pentanoic acid, pentanal, and glycinamide) are shown not to be responsible for inactivation. MAO was inactivated with 2-(n-pentylamino)acetamide(1a),2-(n-pentylamino)[2,2-2H 2]acetamide(1b),and 2-([1,1-2H2]-n-pentylamino)acetamide(1c). Compound 1b exhibited little or no isotope effect on inactivation (kinact/KI) and 1c showed an isotope effect of 4.55 on kinact/KI. These compounds also were found to be excellent substrates for MAO-B; 1b showed no isotope effect, but 1c exhibited an isotope effect of 4.53 on kcat/Km. Incubation of MAO with 2-(n-pentylamino) [2-14C]acetamide followed by dialysis under denaturing conditions resulted in the incorporation of 0.7 equiv of radioactivity per enzyme molecule. The same treatment with 2-([1-14C]-n-pentylamino)acetamide led to the incorporation of 4 equiv of radioactivity into the enzyme. The excess radioactivity bound presumably arises from the [14C]pentanal that is generated during turnover. In order to test this, MAO-B was incubated with [1-14C]pentylamine under similar conditions and 5.9 equiv of radioactivity was incorporated into the denatured enzyme. Therefore, the entire molecule becomes attached to the enzyme during inactivation. By following changes in the flavin absorption spectrum during inactivation with milacemide, it was shown that the flavin becomes reduced; however, denaturation of the inactivation enzyme causes flavin reoxidation under conditions where radioactivity for 2-(n-pentylamino) [2-14C]acetamide remains bound. This suggests that milacemide is oxidized during inactivation and the adduct results from attachment of milacemide to an amino acid residue, not to the flavin cofactor. Inactivation with 2-([1-14C]-n-pentylamino)acetamide produced [14C]pentanoic acid and [14C]-pentylamine in the ratio of 92:8. Inactivation of MAO with 2-(n-pentylamino)[2-14C]acetamide gave [14C]glycinamide and [14C]oxamic acid, further supporting oxidation reactions at both the pentyl side chain and the acetamido methylene. All of these results indicate that milacemide is oxidized at both the pentyl methylene and the acetamido methylene. Pentyl oxidation leads to inactivation, but it is not clear if acetamido methylene oxidation also leads to inactivation (Scheme I).
- Silverman, Richard B.,Nishimura, Kuniko,Lu, Xingliang
-
p. 4949 - 4954
(2007/10/02)
-
- LHRH analogs
-
The present invention relates to novel ""pseudo"" nonapeptide and decapeptide derivatives of LHRH. More particularly the present invention relates to derivatives of LHRH wherein the nitrogen atom of at least one of the amide bonds has been alkylated.
- -
-
-
- Benzodiazepine derivatives, compositions containing them and their use in therapy
-
Compounds of formula (I), and salts and prodrugs thereof wherein: R1 represents optionally substituted C? ??alkyl or C???cycloalkyl; R2 represents an optionally substituted phenyl or pyridyl group; R3 represents C??? alkyl or halo; R? represents C??? cycloalkyl; X is 0, 1, 2 or 3; are CCK and/or gastrin antagonists. They and compositions thereof are therefore useful in therapy.
- -
-
-
- SUBSTITUTED-1,4-DIAZEPINES
-
The invention relates to new 1,4-diazepines of the general formula STR1 in which R 1, R 2 R 3, X and A have the meaning indicated in the specification.The new compounds are intended for use for the treatment of pathological states and diseases in which PAF (platelet activating factor) is involved.
- -
-
-
- Highly Sterically hindered Carbon Acids: The Intrinsic Reactivity of 5,5',5''-Trimethyl- and 3,3',3'',5,5',5''-Hexamethyl-2,2',2'',4,4',4''-Hexanitrotriphenylmethanes
-
Rate constants (kpB,kpBH) for the reversible deprotonation of 5,5',5''-trimethyl- and 3,3',3'',5,5',5''-hexamethyl-2,2',2'',4,4',4''-hexanitrotriphenylmethanes (2 and 3) by primary aliphatic amines, piperidine and morpholine as well as by phenoxide anions and hydroxide anion have been measured in H2O-Me2SO (20:80) at 25 deg C.Comparison of the results obtained with those for 2,2',2'',4,4',4''-hexanitrotriphenylmethane (1a) shows that the introduction of methyl groups in positions adjacent to the nitro groups decreases markedly the thermodynamic acidity of theexocyclic CH group: ΔpK2a1a = 1.68; ΔpK3a1a = 6.48.It is suggested that these decreases are very likely the reflection of a twisting of the nitro groups out of their attached aromatic planes and therefore of a reduced resonance stabilization of the conjugated carbanions C-2 and C-3.Other important steric effects are operating in the ionization of 2 and 3.These arise from the accumulation of ortho-nitro groups in the triphenylmethane system which makes the approach of the base reagents from the exocyclic carbon of 2 and 3 very difficult.The finding of extremely low intrinsic reactivities for 2 and 3 and the observation of a much greater catalytic efficiency of primary amines than of secondary amines in assisting the proton transfers are the two most striking manifestations of these F-strain effects.
- Terrier, Francois,Xiao, Lan,Farrell, Patrick G.,Moskowitz, Danielle
-
p. 1259 - 1263
(2007/10/02)
-
- Cephalosporin compounds
-
Cephalosporin antibiotics having a 3-position substituent of the formula: are described, wherein R1 is hydrogen or certain optionally substituted alkyl groups; Y is --CO-- or --SO2 --; A is optionally substituted phenylene or heterocyclylene; Z is a linking group and Q is a catechol or related ring system. Processes for their preparation and use are described.
- -
-
-
- Kinetics of Amine Addition to Benzylidenemalonodialdehyde in 50percent Me2SO-50percent water
-
The kinetics of the reaction of benzylidenemalonodialdehyde with piperidine, morpholine, n-butylamine, 2-methoxyethylamine, glycinamide, glycine ethyl ester, cyanomethylamine, and semicarbazide have been determined in 50percent aqueous Me2SO at 20 deg C.The reaction leads to a zwitterionic adduct, PhCH(RR'NH(1+))C(CHO)2(1-) (TA(+/-)), that is in fast acid-base equilibrium with the anionic adduct, PhCH(RR'N)C(CHO)2(1-) (TA(1-)).With strongly basic amines at high pH there is also attack of the amine on one of the carbonyl groups, which acts as a rapid preequilibrium.Rate constants for the formation of TA(+/-) (k1) and its reverse (k-1), as well as equilibrium constants (K1 = k1/k-1) and the pKa of TA(+/-) were determined for all the amines.Intrinsic rate constants (k0 = k1 = k-1 when K1 = 1) were calculated.The intrinsic rate constants are lower than those for amine addition to benzylidene Meldrum's acid.This is consistent with the greater role played by resonance in stabilizing TA(+/-) derived from benzylidenemalonodialdehyde.However, k0 for piperidine/morpholine addition to benzylidenemalonodialdehyde is much higher than for the reaction of benzylideneacetylacetone with the same amines, indicating that the rate-depressing effect of intramolecular hydrogen bonding in TA(+/-) derived from benzylidenemalonodialdehyde is much smaller than that in TA(+/-) derived from benzylideneacetylacetone.Even though semicarbazide is an α-effect nucleophile, no enhancement of k1 was observed, but K1, estimated on the basis of a structure-reactivity relationship, is larger than expected based on the pKa of the amine.This result is attributed to a low νnucn value.
- Bernasconi, Claude F.,Stronach, Michael W.
-
p. 1993 - 2001
(2007/10/02)
-
- Kinetics of Amine Addition to Benzylidene-1,3-indandione and Other Vinylic β-Diketones. Effect of Cyclic Structure and Steric Strain on Intrinsic Rate Constants
-
The kinetics of the reactions of benzylidene-1,3-indandione (4) with piperidine, morpholine, n-butylamine, 2-methoxyethylamine, glycinamide, and cyanomethylamine and the reactions of benzylidene-3,5-heptanedione (5), benzylidene-2,6-dimethyl-3,5-heptanedione (6), and benzylidenedibenzoylmethane (7) with piperidine and morpholine have been measured in 50% Me2SO-50% water (v/v) at 20 °C and 0.5 M ionic strength. The reactions lead, in all cases, to the reversible formation of the zwitterionic adduct PhCH(RR′NH+)C(COX)2- (TA±) that is in fast equilibrium with its anion PhCH(RR′N)C-(COX)2-(TA-). Rate constants for nucleophilic addition (k1) and its reverse (k-1) as well as the pKa, of TA± were determined for all reactions. The intrinsic rate constant (k0 = k1 = k-1 when K1 = 1) for amine addition to 4 is abnormally high, whereas k0 for the reactions of 5-7 are abnormally low and similar to k0 in magnitude for amine addition to benzylideneacetylacetone reported previously. The terms "abnormally high" and "abnormally low" refer to positive and negative deviations, respectively, from a plot of log k0 for amine addition to a series of electrophilic olefins of the type PhCH=CYY′ vs log k0 for deprotonation of carbon acids of the type CH2YY′. The high k0 for the reaction of 4 is attributed to its cyclic structure, which assures that the π-overlap required for the stabilization of the adduct is strongly developed in the transition state. The low k0 values for the reactions of 5-7 arise from intramolecular hydrogen bonding, which is strong in TA± but poorly developed in the transition state, and from steric strain in the adduct, which is strongly developed in the transition state. All these effects can be viewed as manifestations of the principle of nonperfect synchronization (PNS).
- Bernasconi, Claude F.,Stronach, Michael W.
-
p. 2222 - 2227
(2007/10/02)
-
- Angiogenesis enhancer
-
The present invention relates to a composition with enhanced angiogenic activity which contains a compound of the formula: wherein R stands for a higher aliphatic hydrocarbon residue, and A stands for hydrogen atom, carboxyl group, hydroxyl group, carbamoyl group which may be substituted or amino group which may be substituted or quaternized. The composition of the present invention has been found to enhance blood vessel formation, which is useful for the treatment of various ischemic diseases, trauma, thermal burns, alopecia, etc.
- -
-
-
- A systematic entropy relationship for the general-base catalysis of the deprotonation of a carbon acid. A quantitative probe of transition-state solvation
-
The general-base-catalyzed deprotonation of a carbon acid, the l-methyl-4-(phenylacetyl)pyridinium cation (pKa = 9.02 at 25 °C), has been investigated for 32 general-base catalysts (25 amines and seven phenoxide ions) in aqueous solution. Amines give a generally scattered Bronsted plot; ring-substituted benzylamines have ?= 0.52, and ring-substituted phenoxides have ?= 0.60, with the phenoxides being more reactive than amines of similar basicity. The temperature dependences of the general-base-catalyzed deprotonation of this carbon acid have been measured over the range 15-45 °C for 12 base catalysts (eight primary, secondary, and tertiary amines; 4-(dimethylamino)pyridine; two phenoxide ions; hydroxide ion). The entropies of activation for these deprotonations show a clean curvilinear dependence upon the entropies of protonation of these base species, with the hydroxide ion being the only significant deviant from this relationship. This observation quantitatively establishes the importance of solvation effects as the major source of deviations that are commonly observed in Bronsted relationships for general-base-catalyzed processes.
- Bunting, John W.,Stefanidis, Dimitrios
-
p. 779 - 786
(2007/10/02)
-
- Synthesis and Chemical Modification of Homoseryl Peptides
-
The readily synthesised N,O-ditritylhomoserine (4) was used for the efficient incorporation of homoserine (1) into peptides; the derived homoseryl peptides were transformed into peptides of canaline and 1,4-diaminobutyric acid using the Mitsunobu reaction.
- Barlos, Kleomenis,Mamos, Petros,Papaioannou, Dionysios,Sanida, Chariklia,Antonopoulos, Christos
-
p. 1258 - 1259
(2007/10/02)
-
- Studies on Pyrazines. 14. The Syntheses of 2,5-Dihydroxypyrazines and Their Derivatives
-
Reaction of phenylglycinamide (1c) with ethyl benzoylformate (2c) in the presence of refluxing ethanolic sodium ethoxide gave 2,5-dihydroxy-3,6-diphenylpyrazine (3i) in 19percent yield.This synthetic method, howewer, was limited to the preparation of 3i.On the other hand, α-aminoamides 1 condensed with α-ketoesters 2 to give the intermediates 5, which were also prepared by condensation of 1 with α-ketalesters 6, followed by hydrolysis of the ketal moeity.Cyclization of 5 with refluxing methanolic sodium methoxide gave only disubstituted 2,5-dihydroxypyrazines 3.Acetylation of 5 with refluxing acetic anhydride/acetic acid led to direct formation of 2,5-diacetoxypyrazines 9.Similarly, compounds 5 could be converted into 2,5-dichloropyrazines 4.
- Adachi, Jiro,Sato, Nobuhiro
-
p. 871 - 875
(2007/10/02)
-
- Heterobicyclic keto- and amino-acids, esters and amides
-
Heterobicyclic glyoxylic acids, L- and DL-heterobicyclic glycines and their derivatives of the formulae STR1 and pharmaceutically acceptable cationic and acid addition salts thereof, wherein R is OR2 or NHR3 ; R2 is hydrogen or alkyl having from one to four carbon atoms; R3 is hydrogen, alkyl having from one to four carbon atoms, alkoxyalkyl having from one to four carbon atoms in each of the alkyl groups or R4 R5 C6 H3 CH2 -- where R4 and R5 are H, OH, F, Cl, Br, I, or alkyl or alkoxy having from one to four carbon atoms R1 is hydrogen, alkyl having from one to four carbon atoms or R4 R5 C6 H3 --; X is oxygen or sulfur; n is 0 or 1 and the broken line represents an optionally present double bond; useful in treatment of diseases and conditions which are characterized by reduced blood flow, reduced oxygen availability or reduced carbohydrate metabolism in the cardiovascular system.
- -
-
-
- DESIGN AND SYNTHESIS OF A MULTI-DETACHABLE BENZHYDRYLAMINE-RESIN FOR SOLID PHASE PEPTIDE SYNTHESIS
-
Peptides with C-terminal α-carboxamides were synthesized from a multi-detachable benzhydrylamine-resin containing a Boc-(4-acetoxy)benzhydrylamine handle of unambiguous origin.The peptides bound to the new resin are stable to trifluoroacetic acid, but are cleavable by hydrogen fluoride, base and nucleophiles to give unprotected or protected peptide fragments.
- Tam, James P.,DiMarchi, Richard D.,Merrifield, R. B.
-
p. 2851 - 2854
(2007/10/02)
-
- Influence de composes a heterocycle azote et particulierement d'azoles non condenses sur des reactions "prebiotiques" de condensation d'acides α-amines induites par les polyphosphates an milieu aqueux
-
In previous experiments aqueous solutions of α-aminoacids in the presence of cyclic or linear polyphosphates, pH range 7-11, yielded up to 40percent of dipeptide but only 0.3-0.5percent of tripeptide .By addition of imidazole the yield of tripeptide could be increased about ten times .Therefore, we have studied for the condensation reaction of glycine the influence of the addition to aqueous solutions 0.1M in glycine and 0.1M in trimethaphosphate at room temperature, pH range 6.7-8.9, of several azoles (pyrrole, pyrazole, imidazole, 1,2,4-triazole and tetrazole), of adenine, guanine, uracil, cytosine, and of several nucleosides (adenosine, guanoside, uridine and cytydine).Among the produts studied, only 1,2,4-triazole and imidazole improve appreciably, by a factor of about 15, the yield of triglycine (up to 7.8percent).While it is very likely that imidazole has played an important role during prebiotic chemical evolution, it is not clear at present whether 1,2,4-triazole has a prebiotic significance.
- Rabinowitz, Joseph,Hampai, Aioub
-
p. 962 - 966
(2007/10/02)
-
