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Isoguanosine (isoG) is a natural structural isomer of guanosine (G) with significant potential for applications in ionophores, genetics, gel formation, and cancer therapy. However, the cost of commercially available isoG on a gram scale is relatively high. To date, a detailed method for the large‐scale preparation of high‐purity isoG has not been reported. This study presented a simple and convenient approach for the large‐scale synthesis of isoG through the diazotization of 2,6‐diaminopurine riboside with sodium nitrite and acetic acid at room temperature. Further, this method could synthesize isoG derivatives (2'‐fluoro‐isoguanosine (1) and 2'‐deoxy‐isoguanosine (2)) from 2,6‐diaminopurine nucleoside derivatives using diazotization. The structural information of natural and modified nucleosides is crucial for the modification and substitution of DNA/RNA. This study obtained the single‐crystal structure of isoG for the first time and analyzed it in detail using microcrystal electron diffraction. The three‐dimensional supramolecular structure of isoG adopted similarly base‐pair motifs from π‐π stacking interaction of diverse layers, intramolecular hydrogen bonding, and distinct hydrogen bonding interactions from sugar residues. This study has contributed to further isoG modification and its applications in medicinal chemistry and materials. [ABSTRACT FROM AUTHOR]

The enzymatic synthesis of nucleoside derivatives is an important alternative to multi-step chemical methods traditionally used for this purpose. Despite several undeniable advantages of the enzymatic approach, there are a number of factors limiting its application, such as the limited substrate specificity of enzymes, the need to work at fairly low concentrations, and the physicochemical properties of substrates—for example, low solubility. This research conducted by our group is dedicated to the advantages and limitations of using purine nucleoside phosphorylases (PNPs), the main enzymes for the metabolic reutilization of purines, in the synthesis of modified nucleoside analogues. In our work, the substrate specificity of PNP from various bacterial sources (mesophilic and thermophilic) was studied, and the effect of substrate, increased temperature, and the presence of organic solvents on the conversion rate was investigated. [ABSTRACT FROM AUTHOR]

Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC50 values ranging from 0.042 μM to 7.530 μM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC50 values of 0.031 μM and 0.094 μM, being about 4.3-fold superior to EFV (EC50 = 0.132 μM) and 1.9-fold superior to NVP (EC50 = 0.181 μM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC50 = 27.9 μM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure–activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections. [ABSTRACT FROM AUTHOR]

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Archaeosine (G+) is an archaea-specific tRNA modification synthesized via multiple steps. In the first step, archaeosine tRNA guanine transglucosylase (ArcTGT) exchanges the G15 base in tRNA with 7-cyano-7-deazaguanine (preQ0). In Euryarchaea, preQ015 in tRNA is further modified by archaeosine synthase (ArcS). Thermococcus kodakarensis ArcS catalyzes a lysine-transfer reaction to produce preQ0-lysine (preQ0-Lys) as an intermediate. The resulting preQ0-Lys15 in tRNA is converted to G+15 by a radical S-adenosyl-L-methionine enzyme for archaeosine formation (RaSEA), which forms a complex with ArcS. Here, we focus on the substrate tRNA recognition mechanism of ArcS. Kinetic parameters of ArcS for lysine and tRNA-preQ0 were determined using a purified enzyme. RNA fragments containing preQ0 were prepared from Saccharomyces cerevisiae tRNAphe-preQ015. ArcS transferred 14C-labeled lysine to RNA fragments. Furthermore, ArcS transferred lysine to preQ0 nucleoside and preQ0 nucleoside 50 -monophosphate. Thus, the L-shaped structure and the sequence of tRNA are not essential for the lysine-transfer reaction by ArcS. However, the presence of D-arm structure accelerates the lysine-transfer reaction. Because ArcTGT from thermophilic archaea recognizes the common D-arm structure, we expected the combination of T. kodakarensis ArcTGT and ArcS and RaSEA complex would result in the formation of preQ0-Lys15 in all tRNAs. This hypothesis was confirmed using 46 T. kodakarensis tRNA transcripts and three Haloferax volcanii tRNA transcripts. In addition, ArcTGT did not exchange the preQ0-Lys15 in tRNA with guanine or preQ0 base, showing that formation of tRNA-preQ0-Lys by ArcS plays a role in preventing the reverse reaction in G+biosynthesis. [ABSTRACT FROM AUTHOR]

Dihydroxyacetone phosphate (DHAP)-dependent aldolases catalyze the aldol addition of DHAP to a variety of aldehydes and generate compounds with two stereocenters. This reaction is useful to synthesize chiral acyclic nucleosides, which constitute a well-known class of antiviral drugs currently used. In such compounds, the chirality of the aliphatic chain, which mimics the open pentose residue, is crucial for activity. In this work, three DHAP-dependent aldolases: fructose-1,6-biphosphate aldolase from rabbit muscle, rhanmulose-1-phosphate aldolase from Thermotoga maritima, and fuculose-1-phosphate aldolase from Escherichia coli, were used as biocatalysts. Aldehyde derivatives of thymine and cytosine were used as acceptor substrates, generating new acyclic nucleoside analogues containing two new stereocenters with conversion yields between 70% and 90%. Moreover, structural analyses by molecular docking were carried out to gain insights into the diasteromeric excess observed. [ABSTRACT FROM AUTHOR]

Recently, graphitic carbon nitride (g-C3N4) has attracted great attention among the most promising materials in heterogeneous catalysis. Herein, we describe an application of ammonium iodide-coated g-C3N4 (NH4I@g-C3N4) as a new and sustainable heterogeneous catalyst for the selective N1-alkylation of pyrimidines. Structural, morphological, and spectroscopic analyses of NH4I@g-C3N4 were carried out through X-ray diffraction (XRD), scanning electronic microscopy (SEM), ultra-violet visible spectroscopy (UV-visible) and Fourier-transform infrared spectroscopy (FTIR). The obtained results prove that the NH4I@g-C3N4 is well prepared. Moreover, it was applied as an efficient catalyst in the synthesis of nucleoside analogs through the N1-alkylation reaction of pyrimidine nucleobases. Several alkylating agents were tested with various parameters to achieve excellent selectivity and high yields. This novel eco-friendly catalyst showed a catalytic activity and good selectivity in the synthesis of nucleoside analogs without noticeable changes in the morphology. [ABSTRACT FROM AUTHOR]

In this study, we have developed a metal‐mediated synthetic method for incorporating the 1,1,2,2‐tetrafluoroethyl (CF2CF2H) motif into unactivated, electron‐rich alkenyl iodides using cross‐coupling reactions. We discovered that the stable Cu(CF2CF2H)(PPh2Me)3 complex, while unreactive with these substrates, serves as a P‐ligated reservoir for the formation of solvent‐stabilized "ligandless" and reactive CuCF2CF2H species. This transformation occurs upon addition of CuBr, which partially scavenges the P‐ligand in the form of CuBr(PPh2Me)3. The resulting in situ generated solvent stabilized "ligandless" system significantly enhances the reactivity of the complex, particularly towards challenging electron‐rich substrates. This advancement enables the synthesis of HCF2CF2‐glycals, as well as nucleosides/nucleobases and arenes. [ABSTRACT FROM AUTHOR]

New homodimers of 1,2,3-triazolyl nucleoside analogs based on 6-methyluracil, which are linked by the polymethylene linker at the N(1) or N(3) atoms, were synthesized. Screening of in vitro antiviral activity against influenza A virus (H1N1) and Coxsackievirus B3 revealed the lead compound that in vitro inhibited the replication of Coxsackievirus B3 with a half-maximal inhibitory concentration (IC50) and a half-maximal cytotoxic concentration (CC50) of 30.1 and >374 µmol L−1, respectively. A dependence of the antiviral activity on the length of the polymethylene linker connecting the 6-methyluracil and 1,2,3-triazolyl-β-d-ribofuranosyl fragments was found. [ABSTRACT FROM AUTHOR]

A direct catalytic stereoselective synthesis of C4' functionalized furanoside and nucleoside derivatives with a tetrasubstituted stereocenter is disclosed. The amine‐catalyzed stereoselective α‐aminomethylation reactions on furanoside‐derived aldehyde derivatives gave the corresponding C4' functionalized D‐ or L‐ribose derivatives in good to excellent yields (67−94%) with up to >20:1 dr. [ABSTRACT FROM AUTHOR]

A concise set of 4‐substituted pyrazolo[3,4‐d]pyrimidine carboriboside analogues was synthesized in a divergent fashion via a central intermediate. An oxaziridine reagent allowed the synthesis of a crucial hydrazine glycon intermediate, which was transformed through a base‐build‐up strategy into the desired intermediate using a commercially available pyrimidine building block. Reaction with a variety of nucleophiles allowed late‐stage diversification. All analogues were evaluated for activity against a representative panel of Trypanosomatida. A methoxy‐substituted analogue displayed single‐digit micromolar activity against two subspecies of Trypanosoma brucei in cellular assays. [ABSTRACT FROM AUTHOR]

DNA is constantly damaged by various external and internal factors. In particular, oxidative damage occurs in a steady state, and 8-oxo-2′-deoxyguanosine (oxodG) is known as the main oxidative damage. OxodG is a strong genotoxic nucleoside and is thought to be involved in the pathogenesis of cancer and neurological diseases. However, a breakthrough method to detect the position of oxodG in DNA has not yet been developed. Therefore, we attempted to develop a novel method to detect oxodG in DNA using artificial nucleosides. Recently, we have succeeded in the recognition of oxodG in DNA by a single nucleotide elongation reaction using nucleoside derivatives based on a purine skeleton with a 1,3-diazaphenoxazine unit. In this study, we developed a new nucleoside derivative with a pyrimidine skeleton in order to further improve the recognition ability and enzymatic reaction efficiency. We, therefore, designed and synthesized 2′-deoxycytidine-1,3-diazaphenoxazine (Cdap) and its triphosphate derivatives. The results showed that it was incorporated into the primer strand relative to the dG template because of its cytidine skeleton, but it was more effective at the complementary position of the oxodG template. These results indicate that the new nucleoside derivative can be considered as one of the new candidates for the detection of oxodG in DNA. [ABSTRACT FROM AUTHOR]

By covalent binding of 1,2,3-triazolyl nucleoside analogues by a polymethylene chain at the N3 atoms, a series of homodimers was synthesized, in which nucleic bases are replaced by quinazoline-2,4-dione moieties connected to the β-D-ribofuranose residues by 1,2,3-triazolylbutyl linkers. Screening of in vitro antiviral activity against influenza A (H1N1) and Coxsackie B3 viruses revealed a lead compound that showed high antiviral activity (IC50 = 11.6 μM) against influenza A/Puerto Rico/8/34 (H1N1) virus and a lead compound that exhibited high antiviral activity (IC50 = 12.2 μM) against enterovirus Coxsackie B3. [ABSTRACT FROM AUTHOR]

Here we report the short synthesis of "reversed" halogenated C-nucleoside (benzimidazole) analogs. Initially, 1,2; 3,4 vicinal diols of D -galactose were acetylated with two different ketones, acetone and cyclohexanone, to furnish acetylated galacto pyranose 1a and 1b, respectively. Subsequently, pyridinium chlorochromate (PCC) was used for the oxidation of C-6 hydroxy- of 1a and 1b to aldehyde 2a and 2b in good yields. Subsequently, the acetylated β- D -galactopyranosyl C-6 aldehydes were reacted with halogen-substituted O-phenylenediamine to furnish reverse C-galactopyranosyl nucleosides 3a to 7a; 3b to 7b. Hitherto, this is the first report on the synthesis of pyranose-based reverse-position C-nucleosides. These newly synthesized C-nucleosides were identified as an anti-leishmanial agent, in vitro, against Leishmania major and Leishmania tropica. The halogen substitution on the benzimidazole moiety and lipophilicity of the acetylated group of C-nucleosides were found to be the key factors for anti-leishmanial activity. For instance, compound 3a, a non-halogenated analogue, was inactive while its bromine-substituted analogue 6a was considerably active against L. major and L. tropica with IC50 = 8.60 ± 0.04 μM and 8.3 ± 0.4 μM, respectively. Moreover, fluorinated nucleoside 4a with low lipophilicity was inactive but its analogue 4b was active against both strains L. major and L. tropica with IC50 = 24.7 ± 0.3 μM and 20.9 ± 0.4 μM, respectively. [ABSTRACT FROM AUTHOR]

Two convergent approaches for synthesizing a new class of nucleoside diphosphate prodrugs bearing different nucleoside analogs are reported herein. The DiPPro‐nucleotides comprise an acyloxybenzyl group in combination with a lipophilic alkyl residue at the β‐phosphate or β‐phosphonate group, respectively. They are selectively cleaved to form their corresponding β‐alkylated nucleoside diphosphate derivatives in chemical and biological hydrolysis studies. In contrast, there is a selective but slow cleavage observed in the hydrolysis of the DiPPro‐compounds bearing two different, nonbioreversible alkyl moieties in human CD4+ T‐lymphocyte CEM/0 cell extracts. In these studies, the delivery of nucleoside monophosphates rather than nucleoside diphosphates is being observed, most likely due to a pure chemical phosphoranhydride cleavage of the β‐phosph(on)ate moiety. The antiviral evaluation of these two types of prodrugs reveals that these compounds exhibit marked anti‐HIV efficacy in HIV‐2‐infected thymidine kinase‐deficient CD4+ CEM T‐cells (CEM/TK−), with significantly better activities (up to 6700‐fold) against HIV‐2 replication than the parent nucleosides. Primer extension assays demonstrate that the β‐dialkylphosphate‐modified nucleoside derivatives, β‐monoalkylated‐diphosphates, and nucleoside diphosphates serve as substrates for HIV reverse transcriptase for the viral DNA elongation. [ABSTRACT FROM AUTHOR]

This article provides an overview of the current strategies for the enantioselective synthesis of modified nucleosides, which have been used in the treatment of various diseases, including viruses. The focus is on the modifications that can be made to different parts of the nucleoside structure to create therapeutically useful compounds. The article discusses the latest developments in the synthesis of cyclic and acyclic nucleosides, highlighting various methods and reactions that can be used to achieve high yields and enantioselectivities. The authors also acknowledge the institutions that supported their research. [Extracted from the article]

This article explores the synthesis and properties of two 2'-deoxyadenosine mimics, dSA and dSO2A, which contain a thieno[3,2-d]pyrimidine ring. The authors aimed to investigate the enzymatic reactions, photophysical properties, and potential incorporation into oligonucleotides of these mimics. The synthesized adenosine mimics demonstrated high enzymatic stability and exhibited different absorption and fluorescence properties compared to natural adenosine. However, while one mimic successfully formed oligonucleotides, the other decomposed under basic conditions. Overall, this study suggests that dSA can be utilized as a stable adenosine congener with fluorescence properties in ON technologies. [Extracted from the article]

This article discusses a Pd-catalyzed cyanation protocol for iodo nucleosides, specifically focusing on the synthesis of three bioactive nucleosides: toyocamycin, sangivamycin, and a mycalisine A precursor. The authors highlight the importance of nucleosides as potential antiviral drugs and the challenges in installing a cyano group in nucleosides. They present a method using inexpensive zinc cyanide as the cyanating source and provide detailed screening studies and experimental results. The study found that Pd2(dba)3 and N,N-dimethylacetamide (DMA) were the most effective catalyst and solvent, respectively, and other cyanating agents did not produce the desired product. The protocol was successfully applied to the synthesis of the desired bioactive nucleosides and has potential applications beyond nucleosides. [Extracted from the article]

This article explores the development of new nucleoside analogues for treating viral infections and cancer. Specifically, it focuses on fluorinated carbocyclic systems, which have shown promise in medicinal and biological chemistry. The authors discuss the synthesis of various analogues with unsaturation and stereoinversion, as well as different reaction methods. The article also highlights the relevance of nucleoside analogues in the context of the COVID-19 pandemic and the development of mRNA vaccines and antiviral medications. The researchers successfully synthesized a small library of fluorinated carbocyclic nucleoside analogues, achieving C2'-C3' unsaturation using Corey-Winter or Eastwood olefination. They also discovered an unusual C1'-C2' alkene scaffold as a side-product, enabling the synthesis of a 1',2'-didehydro 6'-fluorinated carbauridine and carbacytidine. NMR data was used to investigate the conformations of the analogues in solution, revealing that C2'-C3' unsaturation favored a 6'-endo envelope conformation. Biological evaluation of these nucleoside motifs is currently ongoing. [Extracted from the article]

This document is a tribute to the late Professor Ashok K. Prasad from the University of Delhi in India. The authors express their gratitude for Professor Prasad's contributions to the field of chemistry and highlight his expertise and impact on his students and the scientific community. The document serves as a dedication to Professor Prasad's legacy and his significant role in advancing chemistry in India. [Extracted from the article]

This document provides a comprehensive overview of the chemoenzymatic synthesis of arabino-configured bicyclic nucleosides. The authors describe the synthesis process using enzymatic acetylation reactions and other chemical reactions, as well as the use of different enzymes and solvents. The structures of the synthesized compounds were confirmed through spectral data analysis. The document also includes detailed information on the synthesis and characterization of various nucleosides, including data such as melting points, yields, and spectroscopic data. Overall, this study presents an efficient and environmentally friendly method for synthesizing arabino-configured bicyclic nucleosides. [Extracted from the article]

The rapid increase in the antibiotic resistance of microorganisms, capable of causing diseases in humans as destroying cultural heritage sites, is a great challenge for modern science. In this regard, it is necessary to develop fundamentally novel and highly active compounds. In this study, a series of N4-alkylcytidines, including 5- and 6-methylcytidine derivatives, with extended alkyl substituents, were obtained in order to develop a new generation of antibacterial and antifungal biocides based on nucleoside derivatives. It has been shown that N4-alkyl 5- or 6-methylcytidines effectively inhibit the growth of molds, isolated from the paintings in the halls of the Ancient Russian Paintings of the State Tretyakov Gallery, Russia, Moscow. The novel compounds showed activity similar to antiseptics commonly used to protect works of art, such as benzalkonium chloride, to which a number of microorganisms have acquired resistance. It was also shown that the activity of N4-alkylcytidines is comparable to that of some antibiotics used in medicine to fight Gram-positive bacteria, including resistant strains of Staphylococcus aureus and Mycobacterium smegmatis. N4-dodecyl-5- and 6-methylcytidines turned out to be the best. This compound seems promising for expanding the palette of antiseptics used in painting, since quite often the destruction of painting materials is caused by joint fungi and bacteria infection. [ABSTRACT FROM AUTHOR]

Dendrobium huoshanense (D. huoshanense) has been used as functional food supplements and herbal medicines for preventing and managing diseases with a long history in China. Due to its endangered natural resources and huge demand, people tend to cultivate D. huoshanense to protect this species. However, the quality of wild and cultivated herbs of the same species may change. This work quantified and compared the main quality traits and chemical components of wild imitating and greenhouse cultivated D. huoshanense with different growth years. As a result, wild and cultivated D. huoshanense had similar chemical composition, but there are significant differences in the content of many ingredients (polysaccharides, flavonoids, nucleosides, bibenzyls, lignans and volatile compounds). And the contents of many of these components increased with growing years. In addition, multivariate statistical analyses have been applied to classify and evaluate samples from different cultivation modes according to these components. In conclusion, our results demonstrated that the overall quality of greenhouse cultivated D. huoshanense was not as good as wild-grown, but this mode can be a promising and sustainable way of producing D. huoshanense. [ABSTRACT FROM AUTHOR]

Derivatives of 2'‐O‐4'‐C‐Ethylene‐bridged Nucleic Acid (ENA) monomer, a nucleoside used in the preparation of antisense modified oligonucleotides and featuring an alkyl group in position 7', are stereoselectively produced in nine steps from commercially available 3‐O‐benzyl‐4‐(hydroxymethyl)‐1,2‐O‐isopropylidene‐alpha‐D‐ribofuranose. The synthesis relies on a sequence of reactions involving a Tebbe olefination, a key ring‐closing metathesis, and an enol ether reduction. [ABSTRACT FROM AUTHOR]

Methyl 2-O-benzoyl-3,5-di-O-benzyl-α-L-talofuranoside was synthesized from methyl 3,5-di-O-benzyl-1,2-O-isopropylidene-α-L-talofuranoside which was successively treated with 20% hydrochloric acid in aqueous methanol and benzoyl chloride in anhydrous pyridine. Prospects of using methyl 2-O-benzoyl-3,5-di-O-benzyl-α-L-talofuranoside for the synthesis of new modified nucleosides were demonstrated. [ABSTRACT FROM AUTHOR]

Nucleoside analogs require three phosphorylation steps catalyzed by cellular kinases to give their triphosphorylated metabolites. Herein, the synthesis of two types of triphosphate prodrugs of different nucleoside analogs is disclosed. Triphosphates comprising: i) a γ‐phosphate or γ‐phosphonate bearing a bioreversible acyloxybenzyl group and a long alkyl group and ii) γ‐dialkyl phosphate/phosphonate modified nucleoside triphosphate analogs. Almost selective conversion of the former TriPPPro‐compounds into the corresponding γ‐alkylated nucleoside triphosphate derivatives is demonstrated in CEM/0 cell extracts that proved to be stable toward further hydrolysis. The latter γ‐dialkylated triphosphate derivatives lead to the slow formation of the corresponding NDPs. Both types of TriPPPro‐compounds are highly potent in wild‐type CEM/0 cells and more importantly, they exhibit even better activities against HIV‐2 replication in CEM/TK− cell cultures. A finding of major importance is that, in primer extension assays, γ‐phosphate‐modified‐NTPs, γ‐mono‐alkylated‐triphosphates, and NDPs prove to be substrates for HIV‐RT but not for cellular DNA‐polymerases α,γ. [ABSTRACT FROM AUTHOR]

Nucleoside analogues have been the foundation of antiviral therapy over the past few decades. D‐nucleosides with natural stereochemistry occupies the lion share of the marketed antiviral agents. However, much less effort have been put towards the development of L‐nucleosides as antiviral agents. Herein, our effort towards the synthesis of 2′ ‐substituted L‐nucleoside analogues is reported as an emerging class of antiviral agents. Biological activity of the synthesized L‐nucleosided was evaluated against two viruses of importance, tick‐borne encephalitis virus (TBEV) and Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) in adenocarcinomic human alveolar basal epithelial cells (A459) and Vero cells. Ring opening of L‐2, 2′‐Anhydrouridine (2) with various nucleophiles to make several 2'‐substituted L‐nucleosides is the key synthetic outcome. This development has paved the way in the synthesis of many new analogues of 2'‐substituted L‐nucleosides for numerous applications. [ABSTRACT FROM AUTHOR]

China Xihu Longjing tea is famous for its good flavor and quality. However, information on its related metabolites, except for flavonoids, is largely deficient. Different processing methods for China Xihu Longjing tea fixing—by machines at both the first and second step (A1), first step by machine and second step by hand (A2), first step by hand and second step by machine (A3), and by hand at both the first and second step (A4)—were compared using a UHPLC–QE–MS-based metabolomics approach. Liquid chromatography–mass spectrometry was used to analyze the metabolic profiles of the processed samples. A total of 490 metabolites (3 alkaloids, 3 anthracenes, 15 benzene and substituted derivatives, 2 benzopyrans, 13 coumarins and derivatives, 128 flavonoids, 4 furanoid lignans, 16 glycosides and derivatives, 5 indoles and derivatives, 18 isocoumarins and derivatives, 4 chalcones and dihydrochalcones, 4 naphthopyrans, 3 nucleosides, 78 organic acids and derivatives, 55 organooxygen compounds, 5 phenols, 109 prenol lipids, 3 saccharolipids, 3 steroids and steroid derivatives, and 17 tannins) were identified. The different metabolic profiles were distinguished using PCA and OPLS-DA. There were differences in the types and contents of the metabolites, especially flavonoids, furanoid lignans, glycosides and derivatives, organic acids and derivatives, and organooxygen compounds. There was a positive correlation between flavonoid metabolism and amino acid metabolism. However, there was a negative correlation between flavonoid metabolism and amino acid metabolism, which had the same trend as prenol lipid metabolism and tannins. This study provides new valuable information regarding differences in the metabolite profile of China Xihu Longjing tea processed based on machine fixing and on manual fixing methods. [ABSTRACT FROM AUTHOR]

The article titled "Synthesis of 6-Alkylamino-2-alkylthio(alkoxy) Purine Derivatives: Antiplatelet Aggregation Activity Evaluation and 3D-QSAR Analysis" explores the relationship between the structure of purine derivatives and their ability to prevent platelet aggregation. The researchers synthesized 46 purine derivatives and tested their antiplatelet aggregation activity. They found that modifying the substituents on the purine ring could lead to more effective antiplatelet drugs. The study also includes a 3D-QSAR analysis to analyze the structural factors contributing to the activity. The findings provide valuable insights into the potential of these compounds as antiplatelet agents. [Extracted from the article]

Nucleoside analogues are prevalent in drug design and call for more diversified structures. Bicyclo[1.1.1]pentane (BCP) structure has recently found wide applications in drug discovery. However, incorporation of BCP fragment into nucleoside analogues is hitherto unknown. Thus, from readily available BCP-containing building blocks, six new compounds, including pyrimidine nucleoside analogues, purine nucleoside analogues, and C-nucleoside analogues were prepared in 1–4 steps, generally with good yields. [ABSTRACT FROM AUTHOR]

A series of benzofuro‐fused 7‐deazapurine (6H‐furo[2,3‐e]pyrimido[4,5‐b]indole) 2'‐deoxyribo‐ and ribonucleosides was designed and synthesized. The synthesis of key compound 10‐chloro‐6H‐furo[2,3‐e]pyrimido[4,5‐b]indole was based on the Negishi cross‐coupling of iodobenzofurane with zincated 4,6‐dichloropyrimidine followed by azidation and photochemical cyclization. Glycosylation of the heterocycle with either Hoffer's chlorodeoxyribose or protected ribose followed by cross‐coupling or substitution reactions at position 10 gave the desired two sets of final nucleosides that showed moderate to weak cytostatic activity and interesting fluorescence properties. [ABSTRACT FROM AUTHOR]

Amphipathic perylene derivatives are broad-spectrum antivirals against enveloped viruses that act as fusion inhibitors in a light-dependent manner. The compounds target the lipid bilayer of the viral envelope using the lipophilic perylene moiety and photogenerating singlet oxygen, thereby causing damage to unsaturated lipids. Previous studies show that variation of the polar part of the molecule is important for antiviral activity. Here, we report modification of the lipophilic part of the molecule, perylene, by the introduction of 4-, 8-, and 12-carbon alkyls into position 9(10) of the perylene residue. Using Friedel–Crafts acylation and Wolff–Kishner reduction, three 3-acetyl-9(10)-alkylperylenes were synthesized from perylene and used to prepare 9 nucleoside and 12 non-nucleoside amphipathic derivatives. These compounds were characterized as fluorophores and singlet oxygen generators, as well as tested as antivirals against herpes virus-1 (HSV-1) and vesicular stomatitis virus (VSV), both known for causing superficial skin/mucosa lesions and thus serving as suitable candidates for photodynamic therapy. The results suggest that derivatives with a short alkyl chain (butyl) have strong antiviral activity, whereas the introduction of longer alkyl substituents (n = 8 and 12) to the perylenyethynyl scaffold results in a dramatic reduction of antiviral activity. This phenomenon is likely attributable to the increased lipophilicity of the compounds and their ability to form insoluble aggregates. Moreover, molecular dynamic studies revealed that alkylated perylene derivatives are predominately located closer to the middle of the bilayer compared to non-alkylated derivatives. The predicted probability of superficial positioning correlated with antiviral activity, suggesting that singlet oxygen generation is achieved in the subsurface layer of the membrane, where the perylene group is more accessible to dissolved oxygen. [ABSTRACT FROM AUTHOR]

5′-18O labeled RNA oligos are important probes to investigate the mechanism of 2′-O-transphosphorylation reactions. Here we describe a general and efficient synthetic approach to the phosphoramidite derivatives of 5′-18O labeled nucleosides starting from the corresponding commercially available 5′-O-DMT protected nucleosides. Using this method, we prepared 5′-18O-guanosine phosphoramidite in 8 steps (13.2% overall yield), 5′-18O-adenosine phosphoramidite in 9 steps (10.1% overall yield) and 5′-18O-2′-deoxyguanosine phosphoramidite in 6 steps (12.8% overall yield). These 5′-18O labeled phosphoramidites can be incorporated into RNA oligos by solid phase synthesis for determination of heavy atom isotope effects in RNA 2′-O-transphosphorylation reactions. [ABSTRACT FROM AUTHOR]

A variety of ribo-, 2′-deoxyribo-, and 5′-norcarbocyclic derivatives of the 8-aza-7-deazahypoxanthine fleximer scaffolds were designed, synthesized, and screened for antibacterial activity. Both chemical and chemoenzymatic methods of synthesis for the 8-aza-7-deazainosine fleximers were compared. In the case of the 8-aza-7-deazahypoxanthine fleximer, the transglycosylation reaction proceeded with the formation of side products. In the case of the protected fleximer base, 1-(4-benzyloxypyrimidin-5-yl)pyrazole, the reaction proceeded selectively with formation of only one product. However, both synthetic routes to realize the fleximer ribonucleoside (3) worked with equal efficiency. The new compounds, as well as some 8-aza-7-deazapurine nucleosides synthesized previously, were studied against Gram-positive and Gram-negative bacteria and M. tuberculosis. It was shown that 1-(β-D-ribofuranosyl)-4-(2-aminopyridin-3-yl)pyrazole (19) and 1-(2′,3′,4′-trihydroxycyclopent-1′-yl)-4-(pyrimidin-4(3H)-on-5-yl)pyrazole (9) were able to inhibit the growth of M. smegmatis mc2 155 by 99% at concentrations (MIC99) of 50 and 13 µg/mL, respectively. Antimycobacterial activities were revealed for 4-(4-aminopyridin-3-yl)-1H-pyrazol (10) and 1-(4′-hydroxy-2′-cyclopenten-1′-yl)-4-(4-benzyloxypyrimidin-5-yl)pyrazole (6). At concentrations (MIC99) of 40 and 20 µg/mL, respectively, the compounds resulted in 99% inhibition of M. tuberculosis growth. [ABSTRACT FROM AUTHOR]

[4] In 2012, Xie and co-workers reported a ring-closing metathesis and a diethyl aluminum 2,2,6,6-tertramethylpieridinone mediated epoxide isomerization route to construct the five-membered carbocyclic core of Entecavir, and the total synthesis was finished in 10 steps with 21% overall yield. Keywords: Entecavir; synthesis; stereoisomers; stereoselective; hepatitis B EN Entecavir synthesis stereoisomers stereoselective hepatitis B 3109 3112 4 09/11/23 20231004 NES 231004 Graph Hepatitis B is one of the most prevalent viral diseases in the world and about three hundred million individuals worldwide are chronically infected with HBV. At the beginning of our study, we planned to synthesize stereoisomer B ENT1 b by a modified method developed by Bisacchi for the synthesis of Entecavir. In this manuscript, we report the first synthesis of three stereoisomers of Entecavir. [Extracted from the article]

The therapeutic advantages of some platinum complexes as major anticancer chemotherapeutic agents and of nucleoside analogue-based compounds as essential antiviral/antitumor drugs are widely recognized. Red blood cells (RBCs) offer a potential new strategy for the targeted release of therapeutic agents due to their biocompatibility, which can protect loaded drugs from inactivation in the blood, thus improving biodistribution. In this study, we evaluated the feasibility of loading model nucleobase-containing Pt(II) complexes into human RBCs that were highly stabilized by four N-donors and susceptible to further modification for possible antitumor/antiviral applications. Specifically, platinum-based nucleoside derivatives [PtII(dien)(N7-Guo)]2+, [PtII(dien)(N7-dGuo)]2+, and [PtII(dien)(N7-dGTP)] (dien = diethylenetriamine; Guo = guanosine; dGuo = 2′-deoxy-guanosine; dGTP = 5′-(2′-deoxy)-guanosine-triphosphate) were investigated. These Pt(II) complexes were demonstrated to be stable species suitable for incorporation into RBCs. This result opens avenues for the possible incorporation of other metalated nucleobases analogues, with potential antitumor and/or antiviral activity, into RBCs. [ABSTRACT FROM AUTHOR]

Emerging and re-emerging viruses periodically cause outbreaks and epidemics around the world, which ultimately lead to global events such as the COVID-19 pandemic. Thus, the urgent need for new antiviral drugs is obvious. Over more than a century of antiviral development, nucleoside analogs have proven to be promising agents against diversified DNA and RNA viruses. Here, we present the synthesis and evaluation of the antiviral activity of nucleoside analogs and their deglycosylated derivatives based on a hydroxybenzo[4,5]imidazo[1,2-c]pyrimidin-1(2H)-one scaffold. The antiviral activity was evaluated against a panel of structurally and phylogenetically diverse RNA and DNA viruses. The leader compound showed micromolar activity against representatives of the family Coronaviridae, including SARS-CoV-2, as well as against respiratory syncytial virus in a submicromolar range without noticeable toxicity for the host cells. Surprisingly, methylation of the aromatic hydroxyl group of the leader compound resulted in micromolar activity against the varicella-zoster virus without any significant impact on cell viability. The leader compound was shown to be a weak inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase. It also inhibited biocondensate formation important for SARS-CoV-2 replication. The active compounds may be considered as a good starting point for further structure optimization and mechanistic and preclinical studies. [ABSTRACT FROM AUTHOR]

Two new compounds named 4,4′-bis(β-D-glucopyranosyloxy)biphenyl (1) and spirostane-25(27)-en-2α,3β-diol-3-O-β-D-xylopyranosyl(1→3)-β-D-glucopyranosyl(1→4)-β-D-galactopyranoside (2) were isolated from n-butanol extraction part of 80% ethanol extract of Allii Macrostemonis Bulbus. Alongside these, ten known compounds (3–12) were also identified, including a flavonoid glycoside (3), seven steroids (4–10), a nucleoside (11), and a phenylpropanoid glycoside (12) were found. Notably, compounds 3–6 were isolated from this plant for the first time. The structures of all compounds were confirmed using high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D, and 2D NMR spectroscopy. Some of these compounds showed strong antioxidant activity, and compound 1 demonstrated the most potent reduction of ferric ions (Fe3+) with an IC50 value of 0.59 ± 0.18 mg/mL. Compounds 2 and 3 exhibited the highest scavenging activity against superoxide anion radicals (O2−·) with an IC50 value of 0.02 ± 0.01 mg/mL. Additionally, compound 3 displayed substantial scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) with IC50 values of 0.21 ± 0.17 mg/mL and 0.02 ± 0.01 mg/mL, respectively. The discovery of these two new compounds is a reference for identifying Allii Macrostemonis Bulbus quality markers. Moreover, their exceptional antioxidant activity offers a promising avenue for uncovering novel natural antioxidants. [ABSTRACT FROM AUTHOR]

A novel pH-responsive magnetic graphene oxide composite (MGO@PEI-BA) is proposed for the first time as an adsorbent for the rapid capture and detection of nucleosides (cytidine, uridine, guanosine, and adenosine). The morphology, structure, and magnetic properties of the composite were evaluated using various characterization techniques. The results indicated that the composite was successfully fabricated. A series of parameters that affect extraction and elution were optimized through one-factor-at-a-time and Box-Behnken design of response surface methodology (BBD-RSM). The unique layered structures and easily accessible active sites of the composite facilitated molecular transport, resulting in instantaneous equilibrium of nucleosides adsorption within 5 min. Based on this study, a magnetic dispersive micro-solid-phase extraction (MD-μ-SPE) method assisted by the MGO@PEI-BA was developed in combination with UHPLC-UV analysis for the determination of nucleosides in rat urine. Under the optimum conditions, a wide linear range (10–2000 ng mL−1), good linearity (r > 0.99), low detection limits (1–3 ng mL−1), low relative standard deviations (RSDs ≤ 3.9%), and satisfactory recoveries (82.7–96.3%) were achieved. These results demonstrate that the MGO@PEI-BA is an excellent adsorbent for extracting nucleosides from biological samples. [ABSTRACT FROM AUTHOR]

A series of 1,2,3-triazolyl nucleoside analogues bearing N-acetyl-D-glucosamine residue was synthesized by the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction of N1-ω-alkynyl derivatives of uracil, 6-methyluracil, thymine and 3,4,6-tri-O-acetyl-2-deoxy-2-acetamido-β-D-glucopyranosyl azide. Antiviral assays revealed the lead compound 3f which showed both the same activity against the influenza virus A H1N1 (IC50=70.7 µM) as the antiviral drug Rimantadine in control (IC50=77 µM) and good activity against Coxsackievirus B3 (IC50=13.9 µM) which was one and a half times higher than the activity of the antiviral drug Pleconaril in control (IC50=21.6 µM). According to molecular docking simulations, the antiviral activity of the lead compound 3f against Coxsackie B3 virus can be explained by its binding to a key fragment of the capsid surface of this virus. [ABSTRACT FROM AUTHOR]

Various approaches to the synthesis of 3-halopyrazolo[1,5-a]pyrimidines were studied. It is shown that the most effective strategy consists in the construction of the azoloazine core followed by halogenation with N-iodo- or N-bromosuccinimide. A series of 3-halopyrazolo[1,5-a]pyrimidines, which are bioisosteric analogs of natural purine nucleic bases and the drug Triazavirin®, were synthesized using this strategy. The obtained compounds are interesting as precursors of novel C-nucleosides, which can be synthesized by C-C-coupling with (pseudo)ribosides containing a keto group. [ABSTRACT FROM AUTHOR]

Drug-resistant Plasmodium falciparum (Pf) infections are a major burden on the population and the healthcare system. The establishment of Pf resistance to most existing antimalarial therapies has complicated the problem, and the emergence of resistance to artemisinin derivatives is even more concerning. It is increasingly difficult to cure malaria patients due to the limited availability of effective antimalarial drugs, resulting in an urgent need for more efficacious and affordable treatments to eradicate this disease. Herein, new nucleoside analogues including morpholino-nucleoside hybrids and thio-substituted nucleoside derivatives were prepared and evaluated for in vitro and in vivo antiparasitic activity that led a few hits especially nucleoside-thiopyranoside conjugates, which are highly effective against Pf3D7 and PfRKL-9 strains in submicromolar concentration. One adenosine derivative and four pyrimidine nucleoside analogues significantly reduced the parasite burden in mouse models infected with Plasmodium berghei ANKA. Importantly, no significant hemolysis and cytotoxicity towards human cell line (RAW) was observed for the hits, suggesting their safety profile. Preliminary research suggested that these thiosugar-nucleoside conjugates could be used to accelerate the antimalarial drug development pipeline and thus deserve further investigation. [ABSTRACT FROM AUTHOR]

The 4′ position modifications in carbocyclic nucleosides have not been investigated much as potential antiviral agents. Due to the higher ring strain and torsion of the cyclopentyl carbocyclic ring, it is not easy to carry out the modification at the 4′ position. Therefore, there is a need for a procedure that may tackle the synthesis of 4′ position substituted carbocyclic pentyl ring. In this communication, a stereoselective synthesis of 4′‐α‐fluoro‐methyl carbocyclic nucleosides has been reported. A stereoselective synthesis of the 4‐α‐fluoro‐methyl carbocyclic sugar moiety (16) was carried out via carbocyclic ketone 1. The oxidation of the 5‐methyl hydroxy of 9 followed by the aldol condensation gave a diol 11, which via selective protection followed by selective fluorination, yielded a MOM‐protected 4‐α‐fluoro‐methyl carbocyclic ring (16). Compound 16 served as a key intermediate for the synthesis of purines (21&24) and pyrimidine (28&31) nucleosides. The described synthesis may be utilized to construct the various 4′ position modified carbocyclic nucleos(t)ides for an elaborated structure‐activity relationship (SAR) as an antiviral and anticancer agent. [ABSTRACT FROM AUTHOR]

α-heteroaryl acetaldehydes have become important building blocks in the synthesis of synthetic nucleosides. Novel organocatalytic cascades have enabled the rapid generation of nucleosides, which are valuable building blocks in the development of antisense oligonucleotides or as stand-alone antiviral and anticancer therapies, obviating the need for laborious synthetic routes relying on chiral pool starting materials and inefficient synthetic routes. This manuscript describes a robust and scalable protocol to α-heteroaryl acetaldehydes from readily available building blocks. [ABSTRACT FROM AUTHOR]

The condensation of ethylenediamine or o-phenylenediamine with benzaldehyde or p-bromobenz-aldehyde, respectively, gave the corresponding imidazoline or benzimidazole derivative which was subjected to Mannich aminomethylation to produce new nucleobase analogs. α-D-Glucose was converted to peracetyl derivative, followed by treatment with HBr in acetic acid to obtain 1-bromo sugar. Condensation of the latter with nucleobases afforded new protected nucleoside analogs which were hydrolyzed with sodium methoxide in methanol to obtain free nucleoside analogs. The synthesized compounds were identified by FT-IR and 1H and 13C NMR spectroscopy, and their in vitro antimicrobial activity against four types of bacteria and fungi was evaluated. [ABSTRACT FROM AUTHOR]

Lemna minor L. (LM) has been used for measles opacity, rubella itching, edema, and oliguria, and the main active ingredients were flavonoids, namely, apigenin, apigenin‐7‐O‐glucoside, and luteolin‐7‐O‐glucoside. However, few systematic analyses of their constituents have been performed; thus, it was necessary to establish a fast and efficient method to identify the chemical composition of LM. In this study, the UHPLC‐Q‐Exactive Orbitrap mass spectrometry coupled with parallel reaction monitoring was established. Finally, a total of 112 constituents, including 30 dipeptides, 28 nucleosides, 11 amino acids, 10 organic acids, 10 flavonoids, and 23 other compounds, were identified by MS, diagnostic fragment ions, and retention time. One hundred one of those chemicals were first found in LM, which was very beneficial for the further development and utilization of nutriments and the medicinal use of LM. [ABSTRACT FROM AUTHOR]

To improve the water solubility of anti‐human immunodeficiency virus (HIV) agent DB02, an excellent non‐nucleoside reverse‐transcriptase inhibitor (NNRTI) obtained in our previous efforts, we designed and synthesized four phosphate derivatives of DB02 based on the molecular model of DB02 with RT. Here, the antiviral activity of these four derivatives was detected, leading to the discovery of compound P‐2, which possessed a superior potency to the lead compound DB02 against wild‐type HIV‐1 and a variety of HIV‐resistant mutant viruses significantly. Furthermore, the water solubility of P‐2 was nearly 17 times higher than that of DB02, and the pharmacokinetic test in rats showed that P‐2 demonstrate significantly improved oral bioavailablity of 14.6%. Our study showed that the introduction of a phosphate ester group at the end of the C‐2 side chain of DB02 was beneficial to the improvement of its antiviral activity and pharmacokinetic properties, which provided a promising lead for the further development of S‐DACOs type of NNRTIs. [ABSTRACT FROM AUTHOR]

Using various chromatographic methods, seven compounds, including two secoiridoid glycosides; depressine (1) and gentiopicroside (2), one iridoid glycoside; loganic acid (3), two flavone-C-glycosides; isoorientin (4) and isovitexin (5), one xanthone-C-glycoside, mangiferin (6) as well as a nucleoside; adenosine (7) were isolated from the MeOH extract prepared from the aerial parts of Gentiana asclepiadea L. Their structures were elucidated unambiguously by spectroscopic methods such as 1D and 2D NMR as well as HRESIMS. The anti-inflammatory and analgesic activities of the isolated compounds were also evaluated in vitro. Among the tested compounds, 1, 2, and 4 showed potent anti-inflammatory activity through both nitrite and IL-6 pathways at 200 µM. Besides, compound 1 exhibited the highest decrease in PGE2 level, with a higher inhibition rate compared to positive control indomethacin. [ABSTRACT FROM AUTHOR]

Angiogenin (ANG) protein plays a crucial role in angiogenesis, neovascularization, and cancer metastasis in NSCLC (non‐small cell lung cancer) via non‐coding tiRNA. It protects the cell under ER (endoplasmic reticulum) stress‐induced apoptosis through the translational reprogramming process. Although B82 (Curcumin derivatives) induces ER stress‐induced apoptosis, its mechanism of action was not studied. Therefore, it was hypothesized that the ribonucleolytic activity of ANG may be regulated by B82, resulting in modulated ER stress signaling for apoptosis. Hence, we designed and proposed a synthesis scheme for RNA‐based anti‐angiogenic derivatives of 2‐deoxyuridine nucleoside forming peptide bond with amino acids like serine (Ser‐3) and para‐hydroxy‐phenyl glycine (Normtyr‐1) and compared B82 with them to know the binding affinity with ANG, anti‐angiogenic potential, and its probable mechanism of anti‐RNase activity through MD simulation study. Therefore, using Gromos96 43a1 and 43a2 force fields, MD simulation was performed to investigate binding affinity, ligand‐induced molecular surface area change, conformational change, and dynamics of catalytic site residues to predict ligand binding to ANG in this study. The obtained binding free energy (∆Gbind) result showed the total average ∆Gbind as −113.480 ± 1.682 (Normtyr‐1) > −53.038 ± 33.069 (B82) > −27.909 ± 16.438 (Ser‐3) kJ/mole specify role of B82 in regulating ER stress signaling induced apoptosis through ANG ribonucleolytic activity inhibition, suitability of 43a2 force fields and methodology in ligand screening. It shows the crucial role of Leu115 and His13 residue involvement in total ∆Gbind contribution. Hence, based on the MD result, novel conformation of catalytic residues, and ∆Gbind, a promising combination candidate could be proposed for metastatic NSCLC therapy. [ABSTRACT FROM AUTHOR]