19234-66-3Relevant articles and documents
Potent SARS-CoV-2 mRNA Cap Methyltransferase Inhibitors by Bioisosteric Replacement of Methionine in SAM Cosubstrate
Bobi?eva, Olga,Bobrovs, Raitis,Ka?epe, Iveta,Patetko, Liene,Kalni??, Gints,?i?ovs, Mihails,Bula, Anna L.,Grī Nberga, Solveiga,Borodu??is, Mā Rti??,Ramata-Stunda, Anna,Rostoks, Nils,Jirgensons, Aigars,Tā Rs, Kaspars,Jaudzems, Kristaps
, p. 1102 - 1107 (2021)
Viral mRNA cap methyltransferases (MTases) are emerging targets for the development of broad-spectrum antiviral agents. In this work, we designed potential SARS-CoV-2 MTase Nsp14 and Nsp16 inhibitors by using bioisosteric substitution of the sulfonium and amino acid substructures of the cosubstrate S-adenosylmethionine (SAM), which serves as the methyl donor in the enzymatic reaction. The synthetically accessible target structures were prioritized using molecular docking. Testing of the inhibitory activity of the synthesized compounds showed nanomolar to submicromolar IC50 values for five compounds. To evaluate selectivity, enzymatic inhibition of the human glycine N-methyltransferase involved in cellular SAM/SAH ratio regulation was also determined, which indicated that the discovered compounds are nonselective inhibitors of the studied MTases with slight selectivity for Nsp16. No cytotoxic effects were observed; however, this is most likely a result of the poor cell permeability of all evaluated compounds.
Synthesis of 5'-N-(2-[18F]Fluoroethyl)-carboxamidoadenosine: A promising tracer for investigation of adenosine receptor system by PET technique
Lehel,Horvath,Boros,Mikecz,Marian,Szentmiklosi,Tron
, p. 807 - 815 (2000)
5'-N-(2-[18F]Fluoroethyl)-carboxainidoadenosine ([18F]FNECA), a promising 18F-labelled adenosine agonist has been prepared by two different synthetic routes. In the first, [18F]fluoride was reacted with 5'-N,N-ethylene-2',3'-O-isopropylidenecarboxamido-adenosine and after removing the protective group [18F]FNECA was obtained in a low radiochemical yield (1 ± 1%, mean ± sd, n = 7, decay corrected). In the second, 2-[18F]fluoroethylamine was synthesised according to the literature and reacted with 2',3'-O-isopropylideneadenosine-5'-uronic acid in the presence of a coupling agent. The following hydrolysis step provided the [18F]FNECA with a modest radiochemical yield (24 ± 9%, n = 17, based on [18F]fluoride-activity). After purification by preparative reverse phase HPLC 18.9-166.5 MBq (0.51-4.5 mCi) [18F]FNECA was obtained with a specific activity of 2.35 ± 1.14 TBq/mmol (63.5 ± 30.9 Ci/mmol, n = 3). The total synthesis took 200 min and the decay corrected radiochemical yield based on [18F]F- activity was 17 ± 9% (n = 5) with more than 99.9% radiochemical purity. This second route provides sufficient [18F]FNECA for the subsequent biological evaluation using PET-technique.
Tethering small molecules to a phage display library: Discovery of a selective bivalent inhibitor of protein kinase A
Meyer, Scott C.,Shomin, Carolyn D.,Gaj, Thomas,Ghosh, Indraneel
, p. 13812 - 13813 (2007)
We report a noncovalent tethering methodology for the fragment-based selection of bivalent ligands targeting protein kinases. In this approach, a small-molecule warhead, staurosporine, directs a phage display cyclic peptide library to the active site of cAMP-dependent protein kinase (PKA), allowing for targeted library enrichment. A cyclic peptide discovered through this selection, when covalently attached to a staurosporine derivative, displayed a 90-fold increase in affinity for PKA. Moreover, the bivalent inhibitor was shown to be significantly more selective than the starting warhead when tested against a small panel of kinases. Thus our general methodology allows for covalent linkage of known small-molecule ligands to biological libraries for discovering potent bivalent inhibitors of biological targets. Copyright
Deamination of 2′,3′-O-isopropylideneadenosine-5′- carboxylic acid catalyzed by adenosine deaminase (ADA) and adenylate deaminase (AMPDA): Influence of substrate ionization on the activity of the enzymes
Ciuffreda, Pierangela,Alessandrini, Laura,Pavlovic, Radmila,Santaniello, Enzo
, p. 121 - 127 (2007)
Adenosine deaminase (ADA) and adenylate deaminase (AMPDA) catalyze the deamination of 2′,3′-O-isopropylideneadenosine-5′-carboxylic acid to the corresponding inosine derivative and dependence of the rate of enzymatic reaction on the ionization degree of the substrate has been studied at different pH values. Copyright Taylor & Francis Group, LLC.
A METTL3 inhibitor for repairing corneal damage and its drug application
-
Paragraph 0022; 0035-0041, (2022/02/24)
The present invention discloses a METTL3 inhibitor for repairing corneal damage and pharmaceutical application thereof, the METTL3 inhibitor is a compound shown in formula (I) or a tautomer thereof, a racemic, a racemate, an enantiomer and an diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof. METTL3 inhibitors of the present invention for repairing corneal damage. The present invention provides a small molecule compound capable of inhibiting the activity of the METTL3 protein to play a role in repairing corneal damage and its pharmaceutical applications, specifically the application of organic small molecules based on the structure of the METTL3 protein and related drugs. Compounds disclosed in the present invention are a potent METTL3 inhibitor, the compound is capable of inhibiting the formation of m6A modifications very well. Experiments in the present invention can be concluded that the compounds disclosed in the present invention may play a good corneal repair effect by inhibiting the METTL3 protein.
Investigation on 2′,3′- O-Substituted ATP Derivatives and Analogs as Novel P2X3 Receptor Antagonists
Dal Ben, Diego,Buccioni, Michela,Lambertucci, Catia,Marucci, Gabriella,Spinaci, Andrea,Marchenkova, Anna,Abdelrahman, Aliaa,Nistri, Andrea,Müller, Christa E.,Volpini, Rosaria
supporting information, p. 493 - 498 (2019/04/25)
Antagonists of the purinergic P2X3 receptors represent promising drugs for the treatment of inflammation and pain. The ATP derivative 2′,3′-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) has been described as a potent competitive inhibitor of this receptor. In th