- Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities
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Insulin is a lifesaver for millions of diabetic patients. There is a need for new insulin analogues with more physiological profiles and analogues that will be thermally more stable than human insulin. Here, we describe the chemical engineering of 48 insulin analogues that were designed to have changed binding specificities toward isoforms A and B of the insulin receptor (IR-A and IR-B). We systematically modified insulin at the C-terminus of the B-chain, at the N-terminus of the A-chain, and at A14 and A18 positions. We discovered an insulin analogue that has Cα-carboxyamidated Glu at B31 and Ala at B29 and that has a more than 3-fold-enhanced binding specificity in favor of the "metabolic"IR-B isoform. The analogue is more resistant to the formation of insulin fibrils at 37 °C and is also more efficient in mice than human insulin. Therefore, [AlaB29,GluB31,amideB31]-insulin may be interesting for further clinical evaluation.
- Chrudinova, Martina,Halamova, Tereza,Jiracek, Jiri,Kurochka, Andrii,Mitrova, Katarina,Mrzilkova, Karolina,Panikova, Terezie,Picha, Jan,Selicharova, Irena,Zakova, Lenka
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supporting information
p. 14848 - 14859
(2021/10/20)
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- Ammonium Chloride-Promoted Rapid Synthesis of Monosubstituted Ureas under Microwave Irradiation
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Monosubstituted ureas are important scaffolds in organic chemistry. They appear in various biologically active compounds and serve as versatile precursors in synthesis. Monosubstituted ureas were originally prepared using toxic and hazardous phosgene equivalents. Modern methods include transamidation of urea and nucleophilic addition to cyanate salts, both of which suffer from a narrow substrate scope due to the need for a strong acid and prolonged reaction times. We hereby report that ammonium chloride can promote the reaction between amines and potassium cyanate to generate monosubstituted ureas in water. This method proceeds rapidly under microwave irradiation and tolerates a broad range of functional groups. Unlike previous strategies, it is compatible with other nucleophiles, acid-labile moieties, and most of the common protecting groups. The products precipitate out of solution, allowing facile isolation without column chromatography.
- Lan, Chunling Blue,Auclair, Karine
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supporting information
p. 5135 - 5146
(2021/10/19)
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- Chemical Synthesis of the Trisaccharide Epitope of Phenolic Glycolipid-1 Surface Antigen from Mycobacterium leprae
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PGL-1 epitope 1 bearing a p-aminoethylphenol group was efficiently synthesized by using linear synthetic routes. A method for efficient synthesis of oligosaccharides containing rhamnose rings was developed. The chemistry is flexible and could be used for
- Luo, Wan-Yue,Lu, Bin,Zhou, Rong-Ye,Hu, Xiao,Wang, Jin
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p. 10973 - 10979
(2020/09/23)
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- triAZOLOtriAZINE DERIVATIVES AS A2A RECEPTOR ANTAGONISTS
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The present invention provides triazolotriazine derivatives of formula (1) as A2A receptor antagonists. Compounds of formula (1) and pharmaceutical compositions including the compounds can be used for the treatment of disorders related to A2A receptor hyperfunctioning, such as certain types cancers. Compounds of formula (1) and methods of preparing the compounds are disclosed in the invention.
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Page/Page column 52
(2020/01/24)
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- GLYCOPOLYMERS SEQUESTERING CARBOHYDRATE-BINDING PROTEINS
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The invention relates to polymers comprising carbohydrate ligands and moieties, respectively, that bind to carbohydrate-binding proteins (CBPs), as well as to these carbohydrate ligands, and to their use in diagnosis and therapy of diseases that are assoc
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Page/Page column 98; 99
(2018/10/19)
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- N-Urethane protection of amines and amino acids in an ionic liquid
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An efficient, solvent-free protocol for the N-fluorenylmethoxycarbonylation and N-benzyloxycarbonylation of amines is described. The reaction of aliphatic and aromatic amines with FmocOSu and Cbz-Osu in [Bmim][BF4] at room temperature afforded the corresponding N-urethane derivatives in excellent yields and do not require any further purification. The method has been extended to the N-Fmoc and N-Cbz protection of amino acids. Absence of bases, very short reaction times, high yields, selectivity and ease of product separation are some advantages of this protocol.
- Di Gioia,Gagliardi,Leggio,Leotta,Romio,Liguori
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p. 63407 - 63420
(2015/08/11)
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- Synthetic studies towards stachybotrin C
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The preparation of racemic des-hydroxy stachybotrin C is described. Different approaches have been studied. Observations made in the course of the synthesis show the efficiency of the intermolecular cyclization between the diethyl acetal 19 and phenol 12 leading to the benzopyran moiety 17. Georg Thieme Verlag KG · Stuttgart · New York.
- Tumma, Naresh,Jacolot, Maiwenn,Jean, Mickael,Chandrasekhar, Srivari,Van De Weghe, Pierre
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supporting information
p. 2919 - 2922
(2013/02/22)
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- Synthesis, characterization and biological evaluation of ureidofibrate-like derivatives endowed with peroxisome proliferator-activated receptor activity
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A series of ureidofibrate-like derivatives was prepared and assayed for their PPAR functional activity. A calorimetric approach was used to characterize PPARγ-ligand interactions, and docking experiments and X-ray studies were performed to explain the obs
- Porcelli,Gilardi,Laghezza,Piemontese,Mitro,Azzariti,Altieri,Cervoni,Fracchiolla,Giudici,Guerrini,Lavecchia,Montanari,Di Giovanni,Paradiso,Pochetti,Simone,Tortorella,Crestani,Loiodice
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experimental part
p. 37 - 54
(2012/03/09)
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- 1,2,4-Triazine Derivatives, Preparation and Use Thereof in Human Therapy
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The invention concerns 3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives of general formula (I), wherein: R1 and R2, identical or different, represent a branched or linear C1-C7 alkyl or alkenyl radical, a C1/s
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Page/Page column 19
(2008/12/06)
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- Mild debenzylation of aryl benzyl ether with BCl3 in the presence of pentamethylbenzene as a non-lewis-basic cation scavenger
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Scope and limitations of the debenzylation conditions for aryl benzyl ether, which was developed during our synthetic studies on yatakemycin, were investigated. The chemoselective debenzylation proceeds at low temperature with a combination of BCl3 and pentamethylbenzene as a cation scavenger in the presence of various functional groups.
- Okano, Kentaro,Okuyama, Kei-Ichiro,Fukuyama, Tohru,Tokuyama, Hidetoshi
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scheme or table
p. 1977 - 1980
(2009/04/07)
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- 3-AMIDINOBENZENESULFONAMIDE DERIVATIVES, MEDICINAL COMPOSITIONS CONTAINING THE SAME AND INTERMEDIATES IN THE PRODUCTION THEREOF
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The present invention relates to 3-amidinobenzenesulfonamide derivatives represented by the general formula: wherein R1 represents a hydrogen atom or a hydroxy group; Y represents a single bond or an oxygen atom; and R2 represents a lower alkyl group or a group represented by the general formula: (wherein n represents 1 or 2; and T represents a hydrogen atom, a lower acyl group, a halo (lower acyl) group or a group represented by the general formula:-C(=NH)-W (wherein W represents a lower alkyl group)), and pharmaceutically acceptable salts thereof, which have an excellent activated blood coagulation factor X inhibitory activity and are useful as activated blood coagulation factor X inhibitors, and to pharmaceutical compositions comprising the same and intermediates thereof.
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- New submonomers for poly N-substituted glycines (peptoids)
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Five protected submonomers for peptoid synthesis were prepared, including N(in)-BOC-tryptamine, O-t-butyl tyramine, PMC-guanidino- propylamine, 6-amino-6-deoxy-D-galactopyranose diacetonide, and 5-amino-2,2- dimethyl-1,3-dioxane. The first three mimic nat
- Uno, Tetsuo,Beausoleil, Eric,Goldsmith, Richard A.,Levine, Barry H.,Zuckermann, Ronald N.
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p. 1475 - 1478
(2007/10/03)
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- Structure-activity relationship of N-(phenylalkyl)cinnamides as novel NR2B subtype-selective NMDA receptor antagonists
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A novel series of N-(phenylalkyl)cinnamides related to N-(4- phenylbutyl)-3,4-dihydroxy-β-cyanocinnamide (6, an EGFR-K inhibitor with high antiproliferative activity) was synthesized and tested for antagonism at N-methyl-D-aspartate (NMDA) receptor subtypes. Potency and subunit selectivity were assayed by electrical recordings in Xenopus oocytes expressing three binary combinations of cloned rat NMDA receptor subunits: NR1A expressed in combination with either NR2A, NR2B, or NR2C. The N- (phenylalkyl)cinnamides are selective antagonists of NR1(A)/2B receptors. Assayed under steady-state conditions, N-(4-phenylbutyl)-4-hydroxycinnamide (16) has an IC50 value of 77 nM and > 1000-fold selectivity with respect to NR1(A)/2A and NR1(A)/2C receptors. Potency at α1 adrenergic receptors is low for the four cinnamides tested. Inhibition of NR1(A)/2B receptors does not correlate with EGFR and ErbB2/neu tyrosine kinase inhibitor activity. The N-(phenylalkyl)cinnamide series we describe provides a novel and structurally diverse framework for designing new NR2B-selective NMDA antagonists as potential CNS therapeutics.
- Tamiz, Amir P.,Cai, Sui Xiong,Zhou, Zhang-Lin,Yuen, Po-Wai,Schelkun, Robert M.,Whittemore, Edward R.,Weber, Eckard,Woodward, Richard M.,Keana, John F. W.
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p. 3412 - 3420
(2007/10/03)
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- Synthesis of New Glycopeptidomimetics Based on N-Substituted Oligoglycine bearing an N-Linked Lactoside Side-chain
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A new family of model N-substituted oligoglycines (peptoids) containing an N-linked lactoside side-chain was synthesized by a convergent and a reiterative strategy using tert-butyl bromoacetate and primary amines as building blocks.
- Saha, Uttam K.,Roy, Rene
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p. 2571 - 2574
(2007/10/03)
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- Iodonium ion assisted synthesis of a common inner core trisaccharide fragment corresponding to the cell-wall phenolic glycolipid of Mycobacterium kansasii
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The spacer containing trimer 4-(aminoethyl)phenyl) 2,4-di-O-Me-3-O-[2-O-methyl-3-O-(4-O-acetyl-2-O-methyl-α-L-fucopyrano syl)-α-L-rhamnopyranosyl]-α-L-rhamnopyranoside (2) was prepared by stepwise extension of 4-[2-(benzyloxycarbonylamino)ethyl]phenyl 2,4
- Zegelaar-Jaarsveld,Van Der Marel,Van Boom
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p. 10133 - 10148
(2007/10/02)
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- MANIPULATION OF THE CARBOXYL GROUPS OF α-AMINO-ACIDS AND PEPTIDES USING RADICAL CHEMISTRY BASED ON ESTERS OF N-HYDROXY-2-THIOPYRIDONE
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Photolysis of α-amino-acid or peptide esters derived from N-hydroxy-2-thiopyridone in the presence of t-butylthiol affords the expected decarboxylation products in good yield.The reaction can be applied to the α-carboxyl or to the side chain carboxyl of g
- Barton, Derek H. R.,Herve, Yolande,Potier, Pierre,Thierry, Josiane
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p. 5479 - 5486
(2007/10/02)
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Three open chains precursors of a simplified model of a 14-membered cyclopeptide alkaloid, the ansapeptide , 1-oxa-2-isopropyl-3-amino-4,7-dioxo-5,8-diaza-6-benzyl[10] paracyclophane, were prepared, but ring closure failed. A discussion of this failure led to an attempted ring closure of ansapeptides having structures close to the former, but with larger rings. Three 15-, 17- and 18-membered ansapeptides were effectively synthesized. This result confirmed the existence of a special stretching in the 14-membered ring, explaining the difficulties in cyclisation.
- Rocchiccioli,Jarreau,Pais
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p. 2917 - 2926
(2007/10/08)
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