- A new GLP-1 analogue with prolonged glucose-lowering activity in vivo via backbone-based modification at the N-terminus
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Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic hormone with wonderful glucose-lowering activity. However, its clinical use in type II diabetes is limited due to its rapid degradation at the N-terminus by dipeptidyl peptidase IV (DPP-IV). Among the N-terminal modifications of GLP-1, backbone-based modification was rarely reported. Herein, we employed two backbone-based strategies to modify the N-terminus of tGLP-1. Firstly, the amide N-methylated analogues 2-6 were designed and synthesized to make a full screening of the N-terminal amide bonds, and the loss of GLP-1 receptor (GLP-1R) activation indicated the importance of amide H-bonds. Secondly, with retaining the N-terminal amide H-bonds, the β-peptide replacement strategy was used and analogues 7-13 were synthesized. By two rounds of screening, analogue 10 was identified. Analogue 10 greatly improved the DPP-IV resistance with maintaining good GLP-1R activation in vitro, and showed approximately a 4-fold prolonged blood glucose-lowering activity in vivo in comparison with tGLP-1. This modification strategy will benefit the development of GLP-1-based anti-diabetic drugs.
- Bai, Xiaohui,Niu, Youhong,Zhu, Jingjing,Yang, An-Qi,Wu, Yan-Fen,Ye, Xin-Shan
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p. 1163 - 1170
(2016/03/01)
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- One-pot synthesis of orthogonally protected dipeptide selenazoles employing Nα-amino selenocarboxamides and α-bromomethyl ketones
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A simple and efficient protocol for the synthesis of selenazole containing dipeptidomimetics using Nα-amino selenocarboxamides and α-bromomethyl ketones is described. All the compounds made were isolated in good yields and fully characterized.
- Madhu, Chilakapati,Panguluri, Nageswara Rao,Narendra,Panduranga,Sureshbabu, Vommina V.
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supporting information
p. 6831 - 6835
(2015/01/09)
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- Synthesis of N-urethane protected α-aminoalkyl-α-cyanomethyl ketones; Application to the synthesis of 3-substituted 5-amino-1H-pyrazole tethered peptidomimetics
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The preparation of N-protected amino/peptide α-cyanomethyl ketones through cyanation of the corresponding α-bromomethyl ketones is described. The utility of the resulting α-cyanomethyl ketones in the synthesis of 3-substituted-5-amino-1H-pyrazoles has also been demonstrated. In both steps a wide range of N-protected amino/peptide acids has been employed and the products are obtained in good yield. The enantiomeric purity of both the α-cyanomethyl ketones and pyrazoles were confirmed by chiral HPLC analysis of the corresponding Z-protected d- and l-Ala-OH as model substrates. The synthesis of peptide pyrazolecarboxamides is also delineated. Georg Thieme Verlag Stuttgart · New York.
- Sharnabai,Nagendra,Sureshbabu, Vommina V.
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scheme or table
p. 1913 - 1918
(2012/09/25)
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- A one-pot procedure for the preparation of N-9-fluorenylmethyloxycarbonyl- α-amino diazoketones from α-amino acids
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The study describes a new "one-pot" route to the synthesis of N-9-fluorenylmethyloxycarbonyl (Fmoc) α-amino diazoketones. The procedure was tested on a series of commercially available free or side-chain protected α-amino acids employed as precursors. The conversion into the title compounds was achieved by masking and activating the α-amino acids with a single reagent, namely, 9-fluorenylmethyl chloroformate (Fmoc-Cl). The resulting N-protected mixed anhydrides were reacted with diazomethane to lead to the α-amino diazoketones, which were isolated by flash column chromatography in very good to excellent overall yields. The versatility of the procedure was verified on lipophilic α-amino acids and further demonstrated by the preparation of N-Fmoc-α-amino diazoketones also from α-amino acids containing side-chain masking groups, which are orthogonal to the Fmoc one. The results confirmed that tert-butyloxycarbonyl (Boc), tert-butyl (tBu), and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), three acid-labile protecting groups mostly adopted in the solution and solid-phase peptide synthesis, are compatible to the adopted reaction conditions. In all cases, the formation of the corresponding C-methyl ester of the starting amino acid was not observed. Moreover, the proposed method respects the chirality of the starting α-amino acids. No racemization occurred when the procedure was applied to the synthesis of the respective N-Fmoc-protected α-amino diazoketones from l-isoleucine and l-threonine and to the preparation of a diastereomeric pair of N-Fmoc-protected dipeptidyl diazoketones.
- Siciliano, Carlo,De Marco, Rosaria,Guidi, Ludovica Evelin,Spinella, Mariagiovanna,Liguori, Angelo
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p. 10575 - 10582
(2013/02/22)
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- Ultrasound mediated synthesis of 2-amino-1,3-selenazoles derived from Fmoc/Boc/Z-α-amino acids
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A simple and efficient one-pot synthesis of Fmoc/Boc/Z-amino acid derived 2-amino-1,3-selenazoles by the condensation of Nα-urethane protected amino acid derived bromomethyl ketones with selenourea under the influence of ultrasound has been described. Insertion of 2-amino-1,3-selenazole moiety in the side chains of Asp and Glu has also been achieved following the similar protocol. ARKAT USA, Inc.
- Lalithamba, Haraluru S.,Narendra,Naik, Shankar A.,Sureshbabu, Vommina V.
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experimental part
p. 77 - 90
(2010/12/19)
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- Small molecule microarray-facilitated screening of affinity-based probes (AfBPs) for γ-secretase
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A small molecule microarray (SMM) platform is developed herein, which enables high-throughput discovery of affinity-based probes (AfBPs) against γ-secretase.
- Shi, Haibin,Liu, Kai,Xu, Ashley,Yao, Shao Q.
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supporting information; experimental part
p. 5030 - 5032
(2010/01/06)
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- Pseudopeptide, synthesis method, reagent and applications
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The invention concerns a pseudopeptide of at least 6 amino acids comprising at least a unit selected among the general formulae (I) and/or (II) wherein: R1, R2 and R3 each independently of one another represent a side-chain of amino acids and can be identical or different; X represents an oxygen or sulphur atom. The invention also concerns its synthesis process, a reagent containing it, a detection kit comprising such a reagent, a method for detecting an antigen or an antibody using said pseudopeptide, and antibody or and anti-idiotype and finally a therapeutic composition.
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Page/Page column 9; sheet 1
(2010/11/26)
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- Efficient and direct solid phase synthesis of ketomethylenimino and ketomethylenamino peptides
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The reaction between the free amino terminus of a solid-supported peptide and a glyoxal leads to two families of pseudopeptides, the ketomethylenimino and the ketomethylenamino peptides. The aim of this study is the synthesis of pseudopeptides on solid supports, in order to quickly obtain modified peptides. We report a convenient step-by-step synthesis of ketomethylenimino ψ[CO-CH=N] and ketomethylenamino ψ[CO-CH2-NH] peptides. The key is the reaction between the free amino terminus of the supported peptide and a glyoxal-modified amino acid, leading to a ketomethylenimino bond, which can be reduced to a ketomethylenamino bond.
- Bernard, Elise,Vanderesse, Régis
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p. 8603 - 8606
(2007/10/03)
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- Homologation of α-amino acids to β-amino acids: 9-Fluorenylmethyl chloroformate as a carboxyl group activating agent for the synthesis of Nα-protected aminoacyldiazomethanes
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An efficient and stereospecific homologation of urethane-protected α-amino acids to β-amino acids by Arndt-Eistert approach using an equimolar mixture of Fmoc-/Boc-/Z-α-amino acid and 9-fluorenylmethyl chloroformate for the acylation of diazomethane synth
- Kantharaju,Suresh Babu, Vommina V.
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p. 2152 - 2158
(2007/10/03)
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- Convenient and simple homologation of Nα-urethane protected α-amino acids to their β-homologues with concomitant o-nitrophenylesters formation
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The Wolff rearrangement of α-aminodiazoketones derived from Nα-urethane protected α-amino acids in presence of o-nitrophenol catalyzed by silver acetate at low temperature is described. The potential utility of the well-known ketene intermediat
- Ananda,Gopi,Suresh Babu
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p. 790 - 795
(2007/10/03)
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- Solid-phase synthesis of N,N'-unsymmetrically substituted ureas: Application to the synthesis of carbaza peptides
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The synthesis of Boc- or Fmoc-monoprotected propylenediamine derivatives is reported starting from N-protected α-amino acids. The introduction of these building blocks on solid support via the formation of a urea moiety leads to a new pseudopeptide family
- Limal, David,Semetey, Vincent,Dalbon, Pascal,Jolivet, Michel,Briand, Jean-Paul
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p. 2749 - 2752
(2007/10/03)
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- Convenient and simple synthesis of N-{[(9H-fluoren-9- yl)methoxy]carbonyl}-(Fmoc) protected β-amino acids (=homo-α-amino acids) employing Fmoc-α-amino acids and dicyclohexylcarbodiimide(DCC) mixtures
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A simple approach for the homologation of α-amino acids to β-amino acids by the Arndt-Eistert method employing Fmoc-α-amino acid and N, N1- dicyclohexylcarbodiimide (DCC) mixture for the acylation of diazomethane, synthesizing the key intermediates Fmoc-α-amino acyldiazomethanes as crystalline solids is described.
- Ananda,Suresh Babu
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p. 418 - 423
(2007/10/03)
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- Preparation of N-Fmoc-Protected β2- and β3-Amino Acids and Their Use as Building Blocks for the Solid-Phase Synthesis of β-Peptides
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N-Fmoc-Protected (Fmoc = (9H-fluoren-9-ylmethoxy)carbonyl) β-amino acids are required for an efficient synthesis of β-oligopeptides on solid support. Enantiomerically pure Fmoc-β3-amino acids (β3: side chain and NH2 at C(3)(=C(β))) were prepared from Fmoc-protected (S)- and (R)-α-amino acids with aliphatic, aromatic, and functionalized side chains, using the standard or an optimized Arndt-Eistert reaction sequence. Fmoc-β2-Amino acids (β2 side chain at C(2), NH2 at C(3)(=C(β))) configuration bearing the side chain of Ala, Val, Leu, and Phe were synthesized via the Evans' chiral auxiliary methodology. The target β3-heptapeptides 5-8, a β3- pentadecapeptide 9 and a β2-heptapeptide 10 were synthesized on a manual solid-phase synthesis apparatus using conventional solid-phase peptide synthesis procedures (Scheme 3). In the case of β3-peptides, two methods were used to anchor the first β-amino acid: esterification of the ortho-chlorotrityl chloride resin with the first Fmoc-β-amino acid 2 (Method I, Scheme 2) or acylation of the 4-(benzyloxy)benzyl alcohol resin (Wang resin) with the ketene intermediates from the Wolff rearrangement of amino-acid-derived diazo ketone 1 (Method II, Scheme 2). The former technique provided better results, as exemplified by the synthesis of the heptapeptides 5 and 6 (Table 2). The intermediate from the Wolff rearrangement of diazo ketones 1 was also used for sequential peptide-bond formation on solid support (synthesis of the tetrapeptides 11 and 12). The CD spectra of the β2- and β3-peptides 5, 9. and 10 show the typical pattern previously assigned to an (M) 31 helical secondary structure (Fig.). The most intense CD absorption was observed with the pentadecapeptide 9 (strong broad negative Cotton effect at ca. 213 nm); compared to the analogous heptapeptide 5, this corresponds to a 2.5 fold increase in the molar ellipticity per residue!
- Guichard, Gilles,Abele, Stefan,Seebach, Dieter
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p. 187 - 206
(2007/10/03)
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- Synthesis of N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-Protected (Fmoc) β-Amino Acids (= Homo-α-Amino Acids) by Direct Homologation
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The successful application of the Arndt-Eistert protocol starting from commercially available N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-protected (Fmoc) α-amino acids leading to enantiomerically pure N-Fmoc-Protected β-amino acids in only two steps and with high yield is reported.
- Ellmerer-Mueller, Ernst P.,Broessner, Dagmar,Maslouh, Najib,Tako, Andreas
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- Convenient and stereospecific homologation of N-fluorenyl-methoxycarbonyl-α-amino acids to their β-homologues
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A very simple approach to the enantioselective homologation of α-amino acids is presented which is based on the formation of N-Fmoc-aminoacyldiazomethanes with nearly quantitative yields and on the complete retention of both chiral configuration and N-ter
- Leggio, Antonella,Liguori, Angelo,Procopio, Antonio,Sindona, Giovanni
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p. 1969 - 1971
(2007/10/03)
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