- Specificity of lysine: N6-hydroxylase: A hypothesis for a reactive substrate intermediate in the catalytic mechanism
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The recombinant cytoplasmic preparation of lysine: N6-hydroxylase catalyzes the conversion of L-lysine to its N6-hydroxy derivative when supplemented with the cofactors NADPH and FAD. A number of lysine analogs reflecting minor alterations in the inherent structural features of the amino acid as well compounds with relatively high affinity for lysine binding domains in other proteins were examined for their ability to serve as substrates of lysine: N6-hydroxylase. These studies have revealed that the enzyme does not tolerate any change in the structural features of L-lysine, its preferred substrate, with the exception of the replacement of the C(γ)H2-methylene group by sulfur, as in (S)-2-aminoethyl-L-cysteine. L-Norleucine is a potent inhibitor of the enzyme while L-norvaline and L-α-aminobutyric acid do not exhibit such effect, indicating the importance of a C4 hydrophobic side chain for effective interaction with the enzyme. Among the N-alkyl amides of hydrophobic amino acids, only L-norleucine methylamide and L-α-aminobutyric acid ethylamide serve as moderate inhibitors of lysine: N6-hydroxylase. Based on the enzyme's stringent substrate specificity, a mechanism involving the conversion of L-lysine to 2-aminocaprolactam prior to its oxygenation by the 4α-peroxyflavin intermediate in the catalytic cycle is proposed.
- Marrone,Siemann,Beecroft,Viswanatha
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- O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium salts as efficient reagents in active ester synthesis
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The new uronium salts O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium hexafluorophosphate (HSDU) and tetrafluoroborate (TSDU) have been prepared from 1,3-dimethylpropyleneurea (DMPU) and employed in the synthesis of N-hydroxysuccinimide-derived active esters. High yields were obtained at room temperature in short reaction times and no racemization was observed.
- Bailén, Miguel A,Chinchilla, Rafael,Dodsworth, David J,Nájera, Carmen
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- Microporous Molecular Materials from Dipeptides Containing Non-proteinogenic Residues
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Dipeptides with two hydrophobic side chains have proved to be an exceptional source of microporous organic materials, but since previous structures were limited to the incorporation of only proteinogenic residues, their full potential as adsorbents has remained unexplored. Single-crystal XRD data for ten new compounds with non-proteinogenic L-2-aminobutanoic acid and/or L-2-amino-pentanoic acid are presented. The gas-phase accessibility of their crystal pores, with cross-sections of 2.3 to 5.1?, was monitored by CO2 and CH4 adsorption isotherms. Included CO2 was also detected spectroscopically by 2D MAS NMR. An extensive conformational analysis reveals that the use of linear rather than branched side chains (such as L-valine and L-isoleucine) affords peptides with a greater degree of conformational freedom and yields more-flexible channel surfaces that may easily adapt to a series of potential guest molecules.
- Yadav, Vitthal N.,Comotti, Angiolina,Sozzani, Piero,Bracco, Silvia,Bonge-Hansen, Tore,Hennum, Martin,G?rbitz, Carl Henrik
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- POLYMER OF GAMMA-GLUTAMYL TRANSPEPTIDASE CATALYZING HYDROLYSIS-INDUCED CHARGE REVERSAL AND ITS APPLICATION IN THE FIELD OF DRUG DELIVERY
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This present invention relates to a polymer of γ-glutamyl transpeptidase catalyzing hydrolysis-induced charge reversal. The polymer comprises a γ-glutamyl transpeptidase-responsive element represented by Formula (I). When the polymer is used as drug carrier for anticancer drug, it can have a long circulation time in the blood, and can realize a charge reversal from negatively charged or the neutral to positively charged around the tumor blood vessel region, so that the positively charged polymer effectively penetrates deep into the tumor tissue, fast entering into the tumor cells, and greatly improves the therapeutic effect of the drug on the tumor. This overcomes the problems of slow diffusion of traditional polymer drug carriers in tumors and weak interaction with tumor cells, and has great significance in the field of anticancer treatment in the medical field.
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Paragraph 0076
(2020/07/23)
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- Domino Aryne Annulation via a Nucleophilic-Ene Process
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1,2-Benzdiyne equivalents possess the unique property that they can react with two arynophiles through iteratively generated 1,2- and 2,3-aryne intermediates. Upon rational modification on the second leaving group of these aryne precursors, a domino aryne annulation approach was developed through a nucleophilic-ene reaction sequence. Various benzo-fused N-heterocyclic frameworks were achievable under transition metal-free conditions with a broad substrate scope.
- Xu, Hai,He, Jia,Shi, Jiarong,Tan, Liang,Qiu, Dachuan,Luo, Xiaohua,Li, Yang
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supporting information
p. 3555 - 3559
(2018/03/21)
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- Substituted aminopyrimidine compounds and their method and use thereof
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The invention relates to a new aminopyrimidine compound and an application thereof as a drug for treating disorder or diseases related to PI3-kinase abnormity in a free form or a pharmaceutically acceptable salt and preparation form. The invention also relates to a pharmaceutical composition which contains the new aminopyrimidine compound and an application of the pharmaceutical composition in treating mammal disorder or diseases and especially treating human disorder or diseases related to the PI3-kinase abnormity, such as treatment of immunity and inflammatory diseases of PI3-kinase regulation which plays a leading role in a leucocyte function and treatment of proliferative diseases which are related to PI3-kinase activity and include but not limited to leukaemia and solid tumor.
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Paragraph 0576; 0577; 0578; 0579
(2017/12/28)
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- Expanding the peptide β -turn in α γ hybrid sequences: 12 atom hydrogen bonded helical and hairpin turns
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Hybrid peptide segments containing contiguous a and y amino acid residues can form C 12 hydrogen bonded turns which may be consideredas backbone expanded analogues of C 10 OS-turns) found in aa segments. Exploration of the regular hy
- Chatterjee, Sunanda,Vasudev, Prema G.,Raghothama, Srinivasarao,Ramakrishnan, Chandrasekharan,Shamala, Narayanaswamy,Balaram, Padmanabhan
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supporting information; experimental part
p. 5956 - 5965
(2009/09/24)
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- Multiple conformational states in crystals and in solution in αγ hybrid peptides. Fragility of the C12 helix in short sequences
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(Chemical Equation Presented) The conformational properties of foldamers generated from αγ hybrid peptide sequences have been probed in the model sequence Boc-Aib-Gpn-Aib-Gpn-NHMe. The choice of α-aminoisobutyryl (Aib) and gabapentin (Gpn) residues greatl
- Chatterjee, Sunanda,Vasudev, Prema G.,Ananda, Kuppanna,Raghothama, Srinivasarao,Shamala, Narayanaswamy,Balaram, Padmanabhan
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p. 6595 - 6606
(2008/12/22)
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- Aminoacyl-tRNA synthetase inhibitors as potent and synergistic immunosuppressants
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The aminoacyl-tRNA synthetase family of enzymes is the target of many antibacterials and inhibitors of eukaryotic hyperproliferation. In screening analogues of 5′-O-(N-L-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found t
- Van De Vijver, Pieter,Ostrowski, Tomasz,Sproat, Brian,Goebels, Jozef,Rutgeerts, Omer,Van Aerschot, Arthur,Waer, Mark,Herdewijn, Piet
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supporting information; experimental part
p. 3020 - 3029
(2009/04/07)
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- Evaluation of chelating agents as anti-angiogenic therapy through copper chelation
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A set of novel polyamine hexadentate cis,cis-1,3,5,-triaminocyclohexane (tach) chelating agents were synthesized and evaluated in conjunction with a selection of both linear and macrocyclic polyamines as copper chelators for novel anti-angiogenic therapy in an in vitro endothelial cell proliferation assay to assess their cytotoxicity and selectivity. Macrocyclic polyamine 15 exhibited the greatest selective activity in this assay while the tach based ligands exhibited cytotoxicity, but no selectivity. The evaluation of several sets of polyamine donor chelating agents including a selection of novel hexadentate 1,3,5-cis,cis-triaminocyclohexane (tach) based derivatives were performed in an in vitro endothelial cell proliferation assay to assess their cytotoxicity and selectivity as novel anti-angiogenic agents. The selective nature of the anti-angiogenic agents for human umbilical vein endothelial cells (HUVEC) was compared to a normal fibroblast cell line and a human Glioma cell line to evaluate these compounds. Linear tri- and tetra-polyamines were superior to both macrocyclic and the tach based polyamine chelating agents in terms of selectivity of its inhibitory activity toward the proliferation of HUVEC cells compared to the fibroblast and human Glioma cells. The linear polyamine, triethylenetetramine (22), previously reported to possess anti-angiogenic properties failed to demonstrate any selectivity for inhibiting the proliferation of HUVEC cells compared to the fibroblast and human Glioma cells.
- Camphausen, Kevin,Sproull, Mary,Tantama, Steve,Venditto, Vincent,Sankineni, Sandeep,Scott, Tamalee,Brechbiel, Martin W.
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p. 5133 - 5140
(2007/10/03)
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- Combinations of β3 agonists and growth hormone secretagogues
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This invention is directed to pharmaceutical compositions comprising β3adrenergic agonists including (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid and growth hormone or growth hormone secretagogues, prodrugs thereof or pharmaceutically acceptable salts of said compounds or said prodrugs. The invention is also directed to methods of using those compositions in the treatment of obesity, diabetes, hypertension and frailty in animals and particularly in humans.
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Page column 97
(2008/06/13)
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- Treatment of insulin resistance with growth hormone secretagogues
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This invention is directed to methods of treating insulin resistance in a mammal which comprise administering an effective amount of a compound of formula I, where the variables are defined in the specification, or the stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers, or the pharmaceutically acceptable salts and prodrugs thereof to said mammal. The compounds of formula I are growth hormone secretagogues and as such are useful for increasing the level of endogenous growth hormone. In another aspect this invention provides certain intermediates which are useful in the synthesis of the foregoing compounds and certain processes useful for the synthesis of said intermediates and the compounds of formula I. This invention is further directed to methods comprising administering to a human or other animal a combination of a functional somatostatin antagonist such as an alpha-2 adrenergic agonist and a compound of formula I.
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- Heterocyclic compounds
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This invention is directed to compounds of the formula and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintanence of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of formula I.
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- Dipeptides which promote release of growth hormone
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Compounds of formula (I) are growth hormone releasing peptide mimetics which are useful for the treatment and prevention of osteoporosis. STR1
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