7354-93-0

Usage

Chemical structure

A complex chemical compound with a pyrimidine and pentofuranosyl moieties.

Derived from

A nucleoside.

Sulfonyl group

Attached to the pentofuranosyl moiety.

Potential applications

Medicinal chemistry and drug development.

Biological activity

Unique, but further research is needed to fully understand.

Research status

More research is needed to understand its properties and potential uses.

Upstream product

• 362-43-6 2',3'-O-isopropylideneuridine 
• 104-15-4 toluene-4-sulfonic acid 
• 4124-41-8 p-toluenesulfonylanhydride 
• 58-96-8 uridine 
• 98-59-9 p-toluenesulfonyl chloride 

Downstream Products

• 24514-44-1 5'-amino-5'-deoxyuridine 
• 1590439-12-5 2-[4-[[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methylamino]methyl]phenoxy]-N-pyridin-2-ylacetamide 
• 1590439-68-1 (2S,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxy-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]oxolane-2-carboxamide 
• 1590439-64-7 (2S,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxy-N-[(1S)-2-hydroxy-1-phenylethyl]oxolane-2-carboxamide 

Relevant academic research and scientific papers

4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO

Disclosed are halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.

Tightly linked morpholino-nucleoside chimeras: new, compact cationic oligonucleotide analogues

The polyanionic phosphodiester backbone of nucleic acids contributes to high nuclease sensitivity and low cellular uptake and is therefore a major obstacle to the biological application of native oligonucleotides. Backbone modifications, particularly charge alterations is a proven strategy to provide artificial oligonucleotides with improved properties. Here, we describe the synthesis of a new type of oligonucleotide analogues consisting of a morpholino and a ribo- or deoxyribonucleoside in which the 5′-amino group of the nucleoside unit provides the nitrogen of the morpholine ring. The synthetic protocol is compatible with trityl and dimethoxytrityl protecting groups and azido functionality, and was extended to the synthesis of higher oligomers. The chimeras are positively charged in aqueous medium, due to theN-alkylated tertiary amine structure of the morpholino unit.

Novel bisubstrate uridine-peptide analogues bearing a pyrophosphate bioisostere as inhibitors of human O-GlcNAc transferase

Protein O-linked β-D-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), an essential post-translational as well as cotranslational modification, is the attachment of β-D-N-acetylglucosamine to serine and threonine residues of nucleocytoplasmic proteins. An aberrant O-GlcNAc profile on certain proteins has been implicated in metabolic diseases such as diabetes and cancer. Inhibitors of O-GlcNAc transferase (OGT) are valuable tools to study the cell biology of protein O-GlcNAc modification. In this study we report novel uridine-peptide conjugate molecules composed of an acceptor peptide covalently linked to a catalytically inactive donor substrate analogue that bears a pyrophosphate bioisostere and explore their inhibitory activities against OGT by a radioactive hOGT assay. Further, we investigate the structural basis of their activities via molecular modelling, explaining their lack of potency towards OGT inhibition.

Deploying Fluorescent Nucleoside Analogues for High-Throughput Inhibitor Screening

High-throughput small-molecule screening in drug discovery processes commonly rely on fluorescence-based methods including fluorescent polarization and fluorescence/F?rster resonance energy transfer. These techniques use highly accessible instrumentation; however, they can suffer from high false-negative rates and background signals, or might involve complex schemes for the introduction of fluorophore pairs. Herein we present the synthesis and application of fluorescent nucleoside analogues as the foundation for directed approaches for competitive binding analyses. The general approach describes selective fluorescent environment-sensitive (ES) nucleoside analogues that are adaptable to diverse enzymes that act on nucleoside-based substrates. We demonstrate screening a set of uridine analogues and development of an assay for fragment-based lead discovery with the TcdB glycosyltransferase (GT), an enzyme associated with virulence in Clostridium difficile. The uridine-based probe used for this high-throughput screen has a KD value of 7.2 μm with the TcdB GT and shows a >30-fold increase in fluorescence intensity upon binding. The ES-based probe assay is benchmarked against two other screening approaches.

Propargylglycine-based antimicrobial compounds are targets of TolC-dependent efflux systems in Escherichia coli

A library of novel L-propargylglycine-based compounds were designed and synthesized with the goal of inhibiting the growth of Gram-negative bacteria by targeting LpxC, a highly conserved Gram-negative enzyme which performs an essential step in the lipid A biosynthetic pathway. These compounds were designed with and without a nucleoside and had varying tail structures, which modulate their lipophilicity. The synthetic scheme was improved compared to previous methods: a methyl ester intermediate was converted to a hydroxamic acid, which obviated the need for a THP protecting group and improved the yields and purity of the final compounds. Antimicrobial activity was observed for non-nucleoside compounds containing a phenyl propargyl ether tail (5) or a biphenyl tail (6). An MIC of 16 μg/mL was achieved for 6 in Escherichia coli, but inhibition was only possible in the absence of TolC-mediated efflux. Compound 5 had an initial MIC >160 μg/mL in E. coli. Enhancing outer membrane permeability or eliminating efflux reduced the MIC modestly to 100 μg/mL and 80 μg/mL, respectively. These results highlight the importance of hydrophobicity of this class of compounds in developing LpxC inhibitors, as well as the design challenge of avoiding multidrug efflux activity.

4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO

Disclosed are halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.

Efficient synthesis and antifungal investigation of nucleosides’ quaternary ammonium salt derivatives

Quaternary ammonium salts are a group of compounds with diverse biological properties, the most important of which are their antiviral, antibacterial, and antifungal activities. The quaternization reactions of 5'-O-tosyl derivatives of uridine and thymidine with triethylamine, trimethylamine, 4-(N,N-dimethylamino)pyridine, 2-methylpyridine, and pyridine are described in this article. Two of the synthesized compounds are exceptional because they are first of this type that demonstrate concentration-dependent antifungal in vitro activity against two species of the genus Candida in minimal YNB-SG medium. The experimental results have been extended by adding full atom molecular dynamics simulations and substrates and products energies evaluation.

Inhibition of: O -GlcNAc transferase (OGT) by peptidic hybrids

O-GlcNAc transferase (OGT) attaches a GlcNAc moiety on specific substrate proteins using UDP-GlcNAc as the sugar donor. This modification can alter protein function by regulating cellular signaling and transcription pathways in response to altered nutrient availability and stress. Specific inhibitors of OGT would be valuable tools for biological studies and lead structures for therapeutics. The existing OGT inhibitors are mainly derived from the sugar donor substrate, but poor cell permeability and off-target effects limit their use. Here, we describe our progress on OGT inhibition based on substrate peptides identified by array screening. Subsequently, bisubstrate inhibitors were prepared by conjugating these peptides to uridine in various ways. In parallel, an in silico fragment screening was conducted to obtain small molecules targeting the UDP binding pocket. After evaluation of the initial hits, one of these small molecules was elaborated into a novel OGT hybrid inhibitor, as the replacement of uridine. The novel compounds inhibit OGT activity with IC50 values in the micromolar range.

A low-temperature, photoinduced thiol-ene click reaction: A mild and efficient method for the synthesis of sugar-modified nucleosides

Sugar-modified nucleosides are prime synthetic targets in anticancer and antiviral drug development. Radical mediated thiol-ene coupling was applied for the first time on nucleoside enofuranoside derivatives to produce a broad range of thio-substituted d-ribo, -arabino, -xylo and l-lyxo configured pyrimidine nucleosides. In contrast to the analogous reactions of simple sugar exomethylenes, surprisingly, hydrothiolation of nucleoside alkenes under the standard conditions of various initiation methods showed low to moderate yields and very low stereoselectivity. Optimizing the reaction conditions, we have found that cooling the reaction mixture has a significant beneficial effect on both the conversion and the stereoselectivity, and UV-light initiated hydrothiolation of C2′-, C3′- and C4′-exomethylene derivatives of nucleosides at -80 °C proceeded in good to high yields, and, in most cases, in excellent diastereoselectivity. Beyond the temperature, the solvent, the protecting groups on nucleosides and, in some cases, the configuration of the thiols also affected the stereochemical outcome of the additions. The anomalous l-lyxo diastereoselectivity observed upon the addition of 1-thio-β-d-gluco- and galactopyranose derivatives onto C4′,5′-unsaturated uridines is attributed to steric mismatch between the d-ribo C4′-radical intermediates and the β-configured 1-thiosugars.

Design, modeling & synthesis of 1,2,3-triazole-linked nucleoside-amino acid conjugates as potential antibacterial agents

Copper-catalyzed azide-alkyne cycloadditions (CuAAC or click chemistry) are convenient methods to easily couple various pharmacophores or bioactive molecules. A new series of 1,2,3- Triazole-linked nucleoside-amino acid conjugates have been designed and synthesized in 57-76% yields using CuAAC. The azido group was introduced on the 50-position of uridine or the acyclic analogue using the tosyl-azide exchange method and alkylated serine or proparylglycine was the alkyne. Modeling studies of the conjugates in the active site of LpxC indicate they have promise as antibacterial agents.