949-90-6Relevant articles and documents
Specificity of transglutaminase-catalyzed peptide synthesis
St-Jacques, Antony D.,Rachel, Natalie M.,Curry, Dan R.,Gillet, Steve M.F.G.,Clouthier, Christopher M.,Keillor, Jeffrey W.,Pelletier, Joelle N.,Chica, Roberto A.
, p. 53 - 61 (2016)
Biocatalytic methods for peptide synthesis are of high value due to the rapidly increasing approval of peptide-based therapeutics and the need to develop new analogs. Guinea pig liver transglutaminase (gTG2) catalyzes the cross-linking of peptides and proteins via the formation of γ-glutamyl-ε-lysyl isopeptide bonds. In this study, we investigate gTG2-catalyzed peptide bond formation between various amino acid-derived donor and acceptor substrates. Using LC-MS analysis, we demonstrate that gTG2 forms Gly-Xaa and d-Ala-Gly dipeptide products, confirming that its natural transamidation activity can be co-opted for peptide synthesis. An aromatic ester of Gly was the most efficient acyl-donor substrate tested; aromatic esters of d-Ala and l-Ala showed 50-fold lower reactivity or no reactivity, respectively. A computational strategy combining computational protein design algorithms and molecular dynamics simulations was developed to model the binding modes of donor substrates in the gTG2 active site. We show that the inability of gTG2 to efficiently catalyze peptide synthesis from donors containing alanine results from the narrow substrate binding tunnel, which prevents bulkier donors from adopting a catalytically productive binding mode. Our observations pave the way to future protein engineering efforts to expand the substrate scope of gTG2 in peptide synthesis, which may lead to useful biocatalysts for the synthesis of desirable bioactive molecules.
UREA DERIVATIVES AS PYRUVATE KINASE ACTIVATORS
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Paragraph 505-507, (2022/02/15)
The subject matter described herein is directed to pyruvate kinase activating compounds of Formula I and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions comprising the compounds and methods of administering the compounds for the treatment of diseases associated with PKR and/or PKM2, such as pyruvate kinase deficiency, sickle cell disease, and beta-thalassemia.
N-Alkenylation of hydroxamic acid derivatives with ethynyl benziodoxolone to synthesizecis-enamides through vinyl benziodoxolones
Shimbo, Daisuke,Maruyama, Toshifumi,Tada, Norihiro,Itoh, Akichika
supporting information, p. 2442 - 2447 (2021/04/02)
The stereoselective synthesis ofcis-β-N-alkoxyamidevinyl benziodoxolones (cis-β-N-RO-amide-VBXs) fromO-alkyl hydroxamic acids in the presence of an ethynyl benziodoxolone-acetonitrile complex (EBX-MeCN) is reported herein. The reaction was performed under mild conditions including an aqueous solvent, a mild base, and room temperature. The reaction tolerated variousO-alkyl hydroxamic acids derived from carboxylic acids, such as amino acids, pharmaceuticals, and natural products. Vinyl dideuteratedcis-β-N-MeO-amide-VBXs were also synthesized using deuterium oxide as the deuterium source. Valine-derivedcis-β-N-MeO-amide-VBX was stereospecifically derivatized to hydroxamic acid-derivedcis-enamides without the loss of stereoselectivity or reduction in the deuterium/hydrogen ratio.
SN38-containing antibody-drug conjugate
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Paragraph 0119-0121, (2020/10/04)
The invention discloses an SN38-containing antibody-drug conjugate. A series of SN-38-containing ADC molecules are designed on the basis of comprehensive understanding of ADC drugs, and it is shown through experiments that the designed ADC molecules have good antitumor activity.
Hydration of nitriles to amides by a chitin-supported ruthenium catalyst
Matsuoka, Aki,Isogawa, Takahiro,Morioka, Yuna,Knappett, Benjamin R.,Wheatley, Andrew E. H.,Saito, Susumu,Naka, Hiroshi
, p. 12152 - 12160 (2015/02/19)
Chitin-supported ruthenium (Ru/chitin) promotes the hydration of nitriles to carboxamides under aqueous conditions. The nitrile hydration can be performed on a gram-scale and is compatible with the presence of various functional groups including olefins, aldehydes, carboxylic esters and nitro and benzyloxycarbonyl groups. The Ru/chitin catalyst is easily prepared from commercially available chitin, ruthenium(III) chloride and sodium borohydride. Analysis of Ru/chitin by high-resolution transmission electron microscopy indicates the presence of ruthenium nanoparticles on the chitin support.
One-pot synthesis of orthogonally protected dipeptide selenazoles employing Nα-amino selenocarboxamides and α-bromomethyl ketones
Madhu, Chilakapati,Panguluri, Nageswara Rao,Narendra,Panduranga,Sureshbabu, Vommina V.
supporting information, p. 6831 - 6835 (2015/01/09)
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.
Polythiazole linkers as functional rigid connectors: A new RGD cyclopeptide with enhanced integrin selectivity
Ruiz-Rodriguez,Miguel,Preciado,Acosta,Adan,Bidon-Chanal,Luque,Mitjans,Lavilla,Albericio
, p. 3929 - 3935 (2014/11/27)
Polythiazole amino acids clasp linear peptides to generate cyclic derivatives, however, the resulting species are not merely stapled peptides but bear a complex heterocyclic moiety displaying its intrinsic set of interactions. As a proof of concept, a bisthiazole moiety has been grafted onto an RGD sequence to deliver a new cilengitide analogue with improved integrin selectivity and remarkable in vivo antiangiogenic activity.
Core refinement toward permeable β-secretase (BACE-1) inhibitors with low hERG activity
Ginman, Tobias,Viklund, Jenny,Malmstr?m, Jonas,Blid, Jan,Emond, Rikard,Forsblom, Rickard,Johansson, Anh,Kers, Annika,Lake, Fredrik,Sehgelmeble, Fernando,Sterky, Karin J.,Bergh, Margareta,Lindgren, Anders,Johansson, Patrik,Jeppsson, Fredrik,F?lting, Johanna,Gravenfors, Ylva,Rahm, Fredrik
, p. 4181 - 4205 (2013/07/19)
By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 μM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.
Synthesis of gem-diamino acid derivatives by a Hofmann rearrangement
Aresu, Emanuele,Fioravanti, Stefania,Gasbarri, Simona,Pellacani, Lucio,Ramadori, Federico
, p. 977 - 982 (2013/07/05)
Starting from commercially available N-protected l-α-amino acids, N,N′-protected gem-diaminic units were obtained by a two-step methodology. A Hofmann reaction performed using a primary alcohol as the solvent to trap the isocyanate intermediate represents the key step of the new synthetic procedure. Then, the methodology was applied to α-carbamoyl α′-carboxyl aziridines, also functionalized with l-α-amino esters and stable gem-diaminic units characterized by an aziridine ring and by a retro-peptide modification were obtained. The use of the latter units in the retro-peptide chemistry allows to obtain modified peptides containing an aziridine ring able to behave as an electrophilic site and as a biomimetic structural analog of proline.
Enzymatic C-terminal amidation of amino acids and peptides
Nuijens, Timo,Piva, Elena,Kruijtzer, John A.W.,Rijkers, Dirk T.S.,Liskamp, Rob M.J.,Quaedflieg, Peter J.L.M.
experimental part, p. 3777 - 3779 (2012/09/22)
Herein, we describe two versatile and high yielding enzymatic approaches for the conversion of semi-protected amino acid and peptidyl C-terminal α-carboxylic acids into their corresponding amides. In the first approach, the lipase Candida antarctica lipase-B (Cal-B), and in the second approach, the protease Subtilisin A, are used, respectively. We found that by using the ammonium salt of the α-carboxylic acid instead of separate ammonia sources, the enzymatic amidation reactions proceeded much faster without side reactions and gave near to quantitative yields of products.
