68200-68-0

Usage

Uses

Used in Biochemical Research:
5'-Deoxy-5'-iodoguanosine is used as a molecular probe for various studies, particularly in the field of nucleic acid research, due to its unique iodine substituent.
Used in Pharmaceutical Development:
5'-Deoxy-5'-iodoguanosine is used as a precursor for the synthesis of nucleoside analogs and serves as a potential candidate for the development of new pharmaceutical drugs and therapeutic agents, owing to its structural similarity to natural nucleosides.

Upstream product

• 68200-62-4 2',3'-O,O-isopropylidene-5'-deoxy-5'-iodoguanosine 
• 362-76-5 2',3'-isopropylideneguanosine 
• 118-00-3 G 

Downstream Products

• 5151-99-5 S-guanosyl-methionine 
• 1312036-78-4 C₁₇H₂₀N₆O₆PS^(1-)*Na⁽¹⁺⁾ 
• 132628-22-9 5'-deoxy-5'-thioguanosine 
• 4099-84-7 2-amino-9-((2R,3R,4S,5R)-5-(aminomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one 

Relevant academic research and scientific papers

Two-step synthesis of 5′-deoxy-5′-thioguanosine-5′-monophosphorothioate and its incorporation efficiency into 5′-terminus of RNA for preparation of thiol-functionalized RNA

Several 5′-modifications of RNA molecules have been shown to have broad applications in studying RNA structures, mapping RNA-protein interactions, and in vitro selection of catalytic RNAs. While phosphorothioate modification is one of the most popular methods for functionalizing the 5′-terminus of RNA by a transcription or kinase reaction, conjugation of terminal phosphorothioates with fluorophores has been achieved only with a low efficiency. To overcome this limitation, we have developed a two-step synthetic method for 5′-deoxy-5′-thioguanosine-5′-monophosphorothioate by combining two known reactions and measured its incorporation efficiency into the 5′-terminus of RNA by in vitro transcription using T7 RNA polymerase that requires guanosine to efficiently initiate transcription, followed by treatment of alkaline phosphatase, yielding a terminal sulfhydryl group at the 5′-termini of RNA molecules. Since the sulfhydryl group can be used as an alternative to phosphorothioates, our method may provide a useful route to efficiently introduce reporters, such as fluorophores, into the 5′-terminus of RNA via a stable thio-linker, or to tether the oligomer to a solid support.

5′-Phosphorothiolate Dinucleotide Cap Analogues: Reagents for Messenger RNA Modification and Potent Small-Molecular Inhibitors of Decapping Enzymes

The 5′ cap consists of 7-methylguanosine (m7G) linked by a 5′-5′-triphosphate bridge to messenger RNA (mRNA) and acts as the master regulator of mRNA turnover and translation initiation in eukaryotes. Cap analogues that influence mRNA translation and turnover (either as small molecules or as part of an RNA transcript) are valuable tools for studying gene expression, which is often also of therapeutic relevance. Here, we synthesized a series of 15 dinucleotide cap (m7GpppG) analogues containing a 5′-phosphorothiolate (5′-PSL) moiety (i.e., an O-to-S substitution within the 5′-phosphoester) and studied their biological properties in the context of three major cap-binding proteins: translation initiation factor 4E (eIF4E) and two decapping enzymes, DcpS and Dcp2. While the 5′-PSL moiety was neutral or slightly stabilizing for cap interactions with eIF4E, it significantly influenced susceptibility to decapping. Replacing the γ-phosphoester with the 5′-PSL moiety (γ-PSL) prevented β-γ-pyrophosphate bond cleavage by DcpS and conferred strong inhibitory properties. Combining the γ-PSL moiety with α-PSL and β-phosphorothioate (PS) moiety afforded first cap-derived hDcpS inhibitor with low nanomolar potency. Susceptibility to Dcp2 and translational properties were studied after incorporation of the new analogues into mRNA transcripts by RNA polymerase. Transcripts containing the γ-PSL moiety were resistant to cleavage by Dcp2. Surprisingly, superior translational properties were observed for mRNAs containing the α-PSL moiety, which were Dcp2-susceptible. The overall protein expression measured in HeLa cells for this mRNA was comparable to mRNA capped with the translation augmenting β-PS analogue reported previously. Overall, our study highlights 5′-PSL as a synthetically accessible cap modification, which, depending on the substitution site, can either reduce susceptibility to decapping or confer superior translational properties on the mRNA. The 5′-PSL-analogues may find application as reagents for the preparation of efficiently expressed mRNA or for investigation of the role of decapping enzymes in mRNA processing or neuromuscular disorders associated with decapping.

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.

Characterization and Mechanistic Study of the Radical SAM Enzyme ArsS Involved in Arsenosugar Biosynthesis

Arsenosugars are a group of arsenic-containing ribosides that are found predominantly in marine algae but also in terrestrial organisms. It has been proposed that arsenosugar biosynthesis involves a key intermediate 5′-deoxy-5′-dimethylarsinoyl-adenosine (DDMAA), but how DDMAA is produced remains elusive. Now, we report characterization of ArsS as a DDMAA synthase, which catalyzes a radical S-adenosylmethionine (SAM)-mediated alkylation (adenosylation) of dimethylarsenite (DMAsIII) to produce DDMAA. This radical-mediated reaction is redox neutral, and multiple turnover can be achieved without external reductant. Phylogenomic and biochemical analyses revealed that DDMAA synthases are widespread in distinct bacterial phyla with similar catalytic efficiencies; these enzymes likely originated from cyanobacteria. This study reveals a key step in arsenosugar biosynthesis and also a new paradigm in radical SAM chemistry, highlighting the catalytic diversity of this superfamily of enzymes.

5'-PHOSPHOROTHIOLATE MRNA 5'-END (CAP) ANALOGS, MRNA COMPRISING THE SAME, METHOD OF OBTAINING AND USES THEREOF

The present invention relates to nucleotides, analogs of mRNA 5'-end (cap) containing sulfur atom at the position 5' of 7-methylguanosine nucleoside. The disclosed compounds are recognized (bound and non-hydrolyzed) by DcpS enzyme (Decapping Scavenger), and thus may find therapeutic use as inhibitors thereof. DcpS is cap-specific enzyme with pyrophosphatase activity, which was identified as a therapeutic target in the treatment of spinal muscular atrophy (SMA). Some of the compounds disclosed have additional modifications in the phosphate chain, wh ich modulate their affinity for DcpS enzyme. The present invention also relates to mRNAs modified at the 5' end with mRNA 5'-end (cap) analogs containing 5'- phosphorothiolate moiety, which mRNAs have an increased stability and translational activity in cellular conditions, to a method of their preparation, their uses, and to a pharmaceutical formulation containing them, wherein L1 and L2 are independently selected from the group comprising O and S, wherein at least one of L1 and L2 is not O.

A G4·K+ hydrogel that self-destructs

A G4-quartet based hydrogel formed by self-assembly of borate esters of 5′-deoxy-5′-iodoguanosine (5′-IG 2) undergoes in situ cyclization to give 5′-deoxy-N3,5′-cycloguanosine (5′-cG 3). Formation of 5′-cG 3 causes self-destruction of the gel. This intramolecular cyclization can be used to release nucleoside analogs that have been pre-incorporated into the gel network.

Expanding Radical SAM Chemistry by Using Radical Addition Reactions and SAM Analogues

Radical S-adenosyl-l-methionine (SAM) enzymes utilize a [4Fe-4S] cluster to bind SAM and reductively cleave its carbon–sulfur bond to produce a highly reactive 5′-deoxyadenosyl (dAdo) radical. In almost all cases, the dAdo radical abstracts a hydrogen atom from the substrates or from enzymes, thereby initiating a highly diverse array of reactions. Herein, we report a change of the dAdo radical-based chemistry from hydrogen abstraction to radical addition in the reaction of the radical SAM enzyme NosL. This change was achieved by using a substrate analogue containing an olefin moiety. We also showed that two SAM analogues containing different nucleoside functionalities initiate the radical-based reactions with high efficiencies. The radical adduct with the olefin produced in the reaction was found to undergo two divergent reactions, and the mechanistic insights into this process were investigated in detail. Our study demonstrates a promising strategy in expanding radical SAM chemistry, providing an effective way to access nucleoside-containing compounds by using radical SAM-dependent reactions.

A novel route for preparing 5′ cap mimics and capped RNAs: phosphate-modified cap analogues obtained via click chemistry

The significant biological role of the mRNA 5′ cap in translation initiation makes it an interesting subject for chemical modifications aimed at producing useful tools for the selective modulation of intercellular processes and development of novel therapeutic interventions. However, traditional approaches to the chemical synthesis of cap analogues are time-consuming and labour-intensive, which impedes the development of novel compounds and their applications. Here, we explore a different approach for synthesizing 5′ cap mimics, making use of click chemistry (CuAAC) to combine two mononucleotide units and yield a novel class of dinucleotide cap analogues containing a triazole ring within the oligophosphate chain. As a result, we synthesized a library of 36 mRNA cap analogues differing in the location of the triazole ring, the polyphosphate chain length, and the type of linkers joining the phosphate and the triazole moieties. After biochemical evaluation, we identified two analogues that, when incorporated into mRNA, produced transcripts translated with efficiency similar to compounds unmodified in the oligophosphate bridge obtained by traditional synthesis. Moreover, we demonstrated that the triazole-modified cap structures can be generated at the RNA 5′ end using two alternative capping strategies: either the typical co-transcriptional approach, or a new post-transcriptional approach based on CuAAC. Our findings open new possibilities for developing chemically modified mRNAs for research and therapeutic applications, including RNA-based vaccinations.

Supramolecular assemblies of nucleoside functionalized carbon nanotubes: Synthesis, film preparation, and properties

Nucleoside-functionalized multi-walled carbon nanotubes (N-MWCNTs) were synthesized and characterized. A self-organization process using hydrogen bonding interactions was then used for the fabrication of self-assembled N-MWCNTs films free of stabilizing agents, polymers, or surfactants. Membranes were produced by using a simple water-dispersion-based vacuum-filtration method. Hydrogen-bond recognition was confirmed by analysis with IR spectroscopy and TEM images. Restoration of the electronic conduction properties in the N-MWCNTs membranes was performed by removing the organic portion by thermal treatment under an argon atmosphere to give d-N-MWCNTs. Electrical conductivity and thermal gravimetric analysis (TGA) measurements confirmed the efficiency of the annealing process. Finally, oxidative biodegradation of the films N-MWCNTs and d-N-MWCNTs was performed by using horseradish peroxidase (HRP) and low concentrations of H2O2. Our results confirm that functional groups play an important role in the biodegradation of CNT by HRP: N-MWCNTs films were completely biodegraded, whereas for d-N-MWCNTs films no degradation was observed, showing that the pristine CNT undergoes minimal enzyme-catalyzed oxidation This novel methodology offers a straightforward supramolecular strategy for the construction of conductive and biodegradable carbon nanotube films. Conductive and biodegradable films: A self-organization process using hydrogen-bond interactions (see scheme, MWCNT=multiwalled carbon nanotube) is used for the fabrication of conductive and biodegradable carbon nanotube films totally free of stabilizing agents, polymers, or surfactants.

RAS INHIBITORS AND USES THEREOF

Described herein are compounds of Formulae (I)-(II), and pharmaceutically acceptable salts, and pharmaceutical compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating or preventing proliferative diseases such as cancers (e.g., lung cancer, large bowel cancer, pancreas cancer, biliary tract cancer, or endometrial cancer), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases in a subject.