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Queuosine (Q) is a hypermodified 7-deaza-guanosine nucleoside exclusively synthesized by bacteria. This micronutrient and its respective nucleobase form queuine (q) are salvaged by humans either from gut microflora or digested food. Depletion of Q-tRNA in human or mouse cells causes protein misfolding that triggers endoplasmic reticular stress and the activation of the unfolded protein responses. In vivo, this reduces the neuronal architecture of the mouse brain affecting learning and memory. Herein, a sensitive method for quantifying free q and Q in human blood was developed, optimised and validated. After evaluating q/Q extraction efficiency in several different solid-phase sorbents, Bond Elut PBA (phenylboronic acid) cartridges were found to have the highest extraction recovery for q (82%) and Q (71%) from pooled human plasma. PBS with 4% BSA was used as surrogate matrix for method development and validation. An LC–MS/MS method was validated across the concentration range of 0.0003–1 µM for both q and Q, showing excellent linearity (r2 = 0.997 (q) and r2 = 0.998 (Q)), limit of quantification (0.0003 µM), accuracy (100.39–125.71%) and precision (CV% < 15.68%). In a sampling of healthy volunteers (n = 44), there was no significant difference in q levels between male (n = 14; mean = 0.0068 µM) and female (n = 30; mean = 0.0080 µM) participants (p = 0.50). Q was not detected in human plasma. This validated method can now be used to further substantiate the role of q/Q in nutrition, physiology and pathology. [ABSTRACT FROM AUTHOR]

We disclose herein a novel and general radical approach to alkylthiopurines, encompassing 4 types of thiopurines, as well as their corresponding ribosides. This strategy is achieved through visible light‐mediated late‐stage functionalization of the sulfur atoms of mercaptopurines. The in situ‐generated disulfide was proposed as the pivotal neutral intermediate for this transformation. We present herein a novel photo‐mediated homolytic C−S bond formation for the preparation of alkylthiopurines and alkylthiopurine nucleosides. Despite the presence of reactive sites for the Minisci reaction, chemoselective S‐alkylation remained the predominant pathway. This method allows for the late‐stage introduction of a broad spectrum of alkyl groups onto the sulfur atom of unprotective mercaptopurine derivatives, encompassing 2‐, 6‐, and 8‐mercaptopurine rings. Organoborons serve as efficient and eco‐friendly alkylating reagents, providing advantages in terms of readily availability, stability, and reduced toxicity. Further derivatization of the thioetherified nucleosides, together with anti‐tumor assays, led to the discovery of potent anti‐tumor agents with an IC50 value reaching 6.1 μM (Comp. 31 for Jurkat). [ABSTRACT FROM AUTHOR]

AbstractAberrant metabolism of purines and pyrimidines led to development of drugs for treatment of various diseases, such as inflammatory, neurological, cardiovascular, viral infections and cancer. Purine and Pyrimidine Symposia are characterized by close interactions, leading to extensive cross-fertilization on methodology and translating not only from bench-to-bedside, but also between various disciplines such as medicinal chemistry, pharmacology, oncology, virology, rheumatology, biochemistry, pediatrics, cardiology, surgery and immunology. This background was fundamental in our studies on how to optimize application of existing drugs (5-fluorouracil [5FU], thiopurines, antifolates such as methotrexate) but also to support development of novel drugs such as gemcitabine, novel antifolates, S-1, TAS-102 and fluorocyclopentenylcytosine. Knowledge of their metabolism helped to design rational combinations such as of gemcitabine with cisplatin, one of the most widely used drug combinations for various cancers. The combination of 5FU with uridine, led to the development of triacetyluridine registered for emergency treatment of patients with lethal 5FU toxicity. Mechanisms of action were studied by careful analysis of their metabolism, using classical enzyme assays with radioactive precursors and HPLC analysis. Drug metabolism moved from manually operated HPLC systems with UV-detection for peak identification and paper rolls for quantification, to computer-operated HPLC with automatic multi-wavelength and fluorometric peak detection and more recently to ultrasensitive, highly specific mass-spectrometry-based systems. Some aspects, however, never changed; careful analysis of the results and being prepared for the unexpected. The latter actually led to the most interesting results. Investigation of (nucleoside/nucleotide) metabolism remains an exciting field of research. [ABSTRACT FROM AUTHOR]

Nucleoside and polynucleotide cytidine deaminases (CDAs), such as CDA and APOBEC3, share a similar mechanism of cytosine to uracil conversion. In 1984, phosphapyrimidine riboside was characterised as the most potent inhibitor of human CDA, but the quick degradation in water limited the applicability as a potential therapeutic. To improve stability in water, we synthesised derivatives of phosphapyrimidine nucleoside having a CH2 group instead of the N3 atom in the nucleobase. A charge-neutral phosphinamide and a negatively charged phosphinic acid derivative had excellent stability in water at pH 7.4, but only the charge-neutral compound inhibited human CDA, similar to previously described 2'-deoxyzebularine (Ki = 8.0 ± 1.9 and 10.7 ± 0.5 µM, respectively). However, under basic conditions, the charge-neutral phosphinamide was unstable, which prevented the incorporation into DNA using conventional DNA chemistry. In contrast, the negatively charged phosphinic acid derivative was incorporated into DNA instead of the target 2'-deoxycytidine using an automated DNA synthesiser, but no inhibition of APOBEC3A was observed for modified DNAs. Although this shows that the negative charge is poorly accommodated in the active site of CDA and APOBEC3, the synthetic route reported here provides opportunities for the synthesis of other derivatives of phosphapyrimidine riboside for potential development of more potent CDA and APOBEC3 inhibitors.

Here we present a systematic analysis of the synthesis of unsymmetrical disulphides employing 6‐thioguanosine and its mono‐ and dinucleotides by three of the most common strategies: a nucleophilic substitution of the thiol, a thiol exchange reaction with another disulphide and oxidative dehydrogenation coupling reactions of S−H bonds. The exchange reaction was found to be the most efficient approach and could be used not only for nucleosides but also for nucleotides. [ABSTRACT FROM AUTHOR]

A method of ultra-fast liquid chromatography-triple quadrupole/linear ion trap tandem mass spectrometry (UFLC-QTrap-MS/MS) was established for simultaneous determination of 11 nucleosides and 14 amino acids in Lindera aggregata (Sims) Kosterm., which combined with multivariate statistical analysis to evaluate the quality of different medication parts of Lindera aggregata (Sims) Kosterm. from different habitats. The gradient separation was performed on a Waters XBridge Amide column (2.1 mm×100 mm×3.5 μm) with 0.2% formic acid in water (A) and 0.2% formic acid in acetonitrile (B) as the mobile phase, and the mass spectrometric detection was carried out in electrospray positive ion mode under multiple reaction monitoring (MRM)mode. The samples of different habitats and medication parts were comprehensively evaluated by entropy weight ANOVA, PCA, OPLS-DA, HCA, TOPSIS and GRA according to the contents of 25 target constituents. All of the analytes had good linearity in the range of tested concentration with the correlation coefficient not less than 0.992 4. The average recoveries were between 94.86% and 106.47%, with the relative standard deviation (RSD) less than 4.55%. The analysis results showed that there were significant variations among the different medication parts of Lindera aggregata (Sims) Kosterm. samples. The contents of nucleosides and amino acids in tuber were significantly higher than those in taproot and leaf (p<0.05). In terms of nucleoside, tuber had the highest content with an average content of 74.786 μg/g, followed by leaf of 55.401 μg/g and taproot of 36.290 μg/g. The highest content of amino acid was found in tuber with an average content of 50.850 μg/g, followed by the taproot and leaf with an average contents of 43.213 μg/g and 35.676 μg/g, respectively. The samples collected from different parts of Lindera aggregata (Sims) Kosterm. in different regions were classified into three clusters by HCA and PCA according to the contents of nucleotides and amino acids detected. The classification results were satisfactory, indicating that there were obvious differences in the content of nucleosides and amino acids in different parts of the samples. Six different chemicals, namely uridine, alanine, cytosine, xanthine, adenine and guanine, were obtained by VIP co-screening in OPLS-DA model analysis. Comparing the maximum difference values of TOPSIS and GRA, it was found that the maximum difference value of ri in GRA was 12.08%, while Ci in TOPSIS was 53.23%. This method is simple, sensitive and accurate, which provides a reliable and effective technique for the quality control of Lindera aggregata (Sims) Kosterm. [ABSTRACT FROM AUTHOR]

In this article, we present the synthesis and the optical properties of three original molecules as potential fluorescent ribonucleoside analogues incorporating a 1,6-naphthyridin-7(6H)-one scaffold as a fluorescent nucleobase and a 1,2,3-triazole as a linkage. The nucleosides were prepared via a Cu alkyne-azide cycloaddition (CuAAC) reaction between a ribofuranosyl azide and a 4-ethynylpyridine partner. Construction of substituted 1,6-naphthyridin-7(6H)-ones was achieved through two additional steps. Optical property studies were investigated on nucleoside analogues. Powerful fluorescence properties have been evidenced with a remarkable change of emissivity depending on the polarity of the solvent, making these molecules suitable as a new class of artificial fluorescent nucleosides for investigating enzyme binding sites as well as probing nucleic acids. In addition, we are convinced that such analogues could be of great interest in the search for new antiviral or antitumoral drugs based on nucleosides. [ABSTRACT FROM AUTHOR]

α‐d‐2′‐Deoxyribonucleosides are products of the γ‐irradiation of DNA under oxygen‐free conditions and are constituents of anomeric DNA. They are not found as natural building blocks of canonical DNA. Reports on their conformational properties are limited. Herein, the single‐crystal X‐ray structure of α‐d‐2′‐deoxyadenosine (α‐dA), C10H13N5O3, and its conformational parameters were determined. In the crystalline state, α‐dA forms two conformers in the asymmetric unit which are connected by hydrogen bonds. The sugar moiety of each conformer is arranged in a 'clamp'‐like fashion with respect to the other conformer, forming hydrogen bonds to its nucleobase and sugar residue. For both conformers, a syn conformation of the nucleobase with respect to the sugar moiety was found. This is contrary to the anti conformation usually preferred by α‐nucleosides. The sugar conformation of both conformers is C2′‐endo, and the 5′‐hydroxyl groups are in a +sc orientation, probably due to the hydrogen bonds formed by the conformers. The formation of the supramolecular assembly of α‐dA is controlled by hydrogen bonding and stacking interactions, which was verified by a Hirshfeld and curvedness surface analysis. Chains of hydrogen‐bonded nucleobases extend parallel to the b direction and are linked to equivalent chains by hydrogen bonds involving the sugar moieties to form a sheet. A comparison of the solid‐state structures of the anomeric 2′‐deoxyadenosines revealed significant differences of their conformational parameters. [ABSTRACT FROM AUTHOR]

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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]

Plasma nucleosides-pseudouridine (PU) and N²N²-dimethyl guanosine (DMG) predict the progression of type 2 diabetic kidney disease (DKD) to end-stage renal disease, but the mechanisms underlying this relationship are not well understood. We used a well-characterized model of type 2 diabetes (db/db mice) and control nondiabetic mice (db/m mice) to characterize the production and excretion of PU and DMG levels using liquid chromatography-mass spectrometry. The fractional excretion of PU and DMG was decreased in db/db mice compared with control mice at 24 wk before any changes to renal function. We then examined the dynamic changes in nucleoside metabolism using in vivo metabolic flux analysis with the injection of labeled nucleoside precursors. Metabolic flux analysis revealed significant decreases in the ratio of urine-to-plasma labeling of PU and DMG in db/db mice compared with db/m mice, indicating significant tubular dysfunction in diabetic kidney disease. We observed that the gene and protein expression of the renal tubular transporters involved with nucleoside transport in diabetic kidneys in mice and humans was reduced. In conclusion, this study strongly suggests that tubular handling of nucleosides is altered in early DKD, in part explaining the association of PU and DMG with human DKD progression observed in previous studies. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Central China Normal University is the property of Huazhong Normal University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

ABSTRACTAlthough smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.

Cyclic nucleotide binding domains (CNB) confer allosteric regulation by cAMP or cGMP to many signaling proteins, including PKA and PKG. PKA of phylogenetically distant Trypanosoma is the first exception as it is cyclic nucleotide-independent and responsive to nucleoside analogues (Bachmaier et al., 2019). Here, we show that natural nucleosides inosine, guanosine and adenosine are nanomolar affinity CNB ligands and activators of PKA orthologs of the important tropical pathogens Trypanosoma brucei, Trypanosoma cruzi, and Leishmania. The sequence and structural determinants of binding affinity, -specificity and kinase activation of PKAR were established by structure-activity relationship (SAR) analysis, co-crystal structures and mutagenesis. Substitution of two to three amino acids in the binding sites is sufficient for conversion of CNB domains from nucleoside to cyclic nucleotide specificity. In addition, a trypanosomatid-specific C-terminal helix (αD) is required for high affinity binding to CNB-B. The αD helix functions as a lid of the binding site that shields ligands from solvent. Selectivity of guanosine for CNB-B and of adenosine for CNB-A results in synergistic kinase activation at low nanomolar concentration. PKA pulldown from rapid lysis establishes guanosine as the predominant ligand in vivo in T. brucei bloodstream forms, whereas guanosine and adenosine seem to synergize in the procyclic developmental stage in the insect vector. We discuss the versatile use of CNB domains in evolution and recruitment of PKA for novel nucleoside-mediated signaling.

The title compound, C10H13N5O4·2C2H6OS, which is of interest with respect to its biological activity, at 183 K has orthorhombic (P212121) crystal symmetry. The structure displays a network of intermolecular N—H...N, N—H...O and O—H...O hydrogen bonds. 2′-Deoxyguanosine molecules are linked to each other and to the two dimethyl sulfoxide solvent molecules by hydrogen bonding.

The search for new drugs has been greatly accelerated by the emergence of new viruses and drug-resistant strains of known pathogens. Nucleoside analogues (NAs) are a prospective class of antivirals due to known safety profiles, which are important for rapid repurposing in the fight against emerging pathogens. Recent improvements in research methods have revealed new unexpected details in the mechanisms of action of NAs that can pave the way for new approaches for the further development of effective drugs. This review accounts advanced techniques in viral polymerase targeting, new viral and host enzyme targeting approaches, and prodrug-based strategies for the development of antiviral NAs.

Nucleoside reverse transcriptase inhibitors are the first class of drugs to be approved by the FDA for the suppression of HIV-1 and are widely used for this purpose in combination with drugs of other classes. Despite the progress in HIV-1 treatment, there is still the need to develop novel efficient antivirals. Here the efficiency of HIV-1 inhibition by a set of original 5-substituted uridine nucleosides was studied. We used the replication deficient human immunodeficiency virus (HIV-1)-based lentiviral particles and identified that among the studied compounds, 2′,3′-isopropylidene-5-iodouridine was shown to cause anti-HIV-1 activity. Importantly, no toxic action of this compound against the cells of T-cell origin was found. We determined that this compound is significantly more efficient at suppressing HIV-1 compared to Azidothymidine (AZT) when taken at the high non-toxic concentrations. We did not find any profit when using AZT in combination with 2′,3′-isopropylidene-5-iodouridine. 2′,3′-Isopropylidene-5-iodouridine acts synergistically to repress HIV-1 when combined with the CDK4/6 inhibitor Palbociclib in low non-toxic concentration. No synergistic antiviral action was detected when AZT was combined with Palbociclib. We suggest 2′,3′-isopropylidene-5-iodouridine as a novel perspective non-toxic compound that may be used for HIV-l suppression. [ABSTRACT FROM AUTHOR]

Dengue fever is a viral ailment mostly found in tropical and sub-tropical communities. Dengue fever is spread by the mosquito Aedes aegypti. According to WHO reports, more than 12,000 people perish because of this disease yearly. At present, there is no officially certified drug for the cure of dengue. Dengue virus (DENV) holds four distinct serotypes and hence the development of a single molecule effective against all these types is a difficult task. Various new molecules have been developed against DENV. In this review, we have summarised new chemical scaffolds that have been tested against DENV. New molecules addressed in this review can be considered as a lead compound for upcoming drug development against DENV. [ABSTRACT FROM AUTHOR]

Ophiocordyceps sinensis is a highly valued medicinal fungus and has been used as a traditional Chinese medicine (TCM) to treat asthma and respiratory, kidney, and other diseases for centuries. Due to its medical benefit and scarcity of natural resource, the anamorph mycelium is considered to be a useful substitute for natural O. sinensis. Here, the isolate mycelium from the fruit body of natural O. sinensis was identified to be the anamorph of O. sinensis using single-gene (wc-1 gene) and multi-locus sequence typing (MLST) of 3 genes (ITS, nrSSU, and β-tubulin) based molecular phylogenetic analysis. Biomass assay showed that the log phase occurred in 30–50 days of culture in media. Lots of aerial mycelium was produced on the 60-day potato dextrose agar (PDA) culture and was found to be sticky into lumps with numerous conidia under a scanning electron microscope (SEM) and an optical microscopy. Conidia were polymorphic, measuring about 1.94–5.83 × 1.58–5.57 µm in size, and could be distinguished from other filamentous fungi. Besides, the number of blastospores increased in the 30–60 day potato dextrose broth (PD) liquid culture. No conidia or blastospores were observed in the early stages in PDA media. So the mycelium would initially grow in a polar growth pattern, followed by budding growth or/and conidiogenesis in media. Moreover, some interesting and significant observations revealed that conidial and hyphal fusion occurred, which would play important roles in nutrition utilization, reproduction, and hyphal growth in this isolate. Moreover, 12 sporulation-related genes were screened using our RNA-seqs of O. sinensis, and the mRNA levels were assayed between 45-day and 90-day culture using quantitative real-time PCR(qPCR). Four of them, including fbA, skn7, abaA, and serine/threonine-protein kinase MAK gene, had higher levels of expression in the 45-day culture than in the 90-day culture. Besides, nucleoside components were detected using high-performance liquid chromatography analysis (HPLC). Our findings would aid in understanding O. sinensis's asexual reproduction and hyphal growth in media, as well as the use of the anamorph mycelium as a substitute for natural O. sinensis. [ABSTRACT FROM AUTHOR]

Efforts to fully understand pharmacological differences between G protein-coupled receptor (GPCR) species homologues are generally not pursued in detail during the drug development process. To date, many GPCRs that have been successfully targeted are relatively well-conserved across species in amino acid sequence and display minimal variability of biological effects. However, the A3 adenosine receptor (AR), an exciting drug target for a multitude of diseases associated with tissue injury, ischemia, and inflammation, displays as little as 70% sequence identity among mammalian species (e.g., rodent vs. primate) commonly used in drug development. Consequently, the pharmacological properties of synthetic A3AR ligands vary widely, not only in binding affinity, selectivity, and signaling efficacy, but to the extent that some function as agonists in some species and antagonists in others. Numerous heterocyclic antagonists that have nM affinity at the human A3AR are inactive or weakly active at the rat and mouse A3ARs. Positive allosteric modulators, including the imidazo [4,5-c]quinolin-4-amine derivative LUF6000, are only active at human and some larger animal species that have been evaluated (rabbit and dog), but not rodents. A3AR agonists evoke systemic degranulation of rodent, but not human mast cells. The rat A3AR undergoes desensitization faster than the human A3AR, but the human homologue can be completely re-sensitized and recycled back to the cell surface. Thus, comprehensive pharmacological evaluation and awareness of potential A3AR species differences are critical in studies to further understand the basic biological functions of this unique AR subtype. Recombinant A3ARs from eight different species have been pharmacologically characterized thus far. In this review, we describe in detail current knowledge of species differences in genetic identity, G protein-coupling, receptor regulation, and both orthosteric and allosteric A3AR pharmacology. [ABSTRACT FROM AUTHOR]

The title compound, C10H13N5O4·2C2H6OS, which is of interest with respect to its biological activity, at 183 K has ortho-rhombic (P212121) crystal symmetry. The structure displays a network of inter-molecular N--H...N, N--H...O and O--H...O hydrogen bonds. 2'-Deoxyguanosine molecules are linked to each other and to the two dimethyl sulfoxide solvent molecules by hydrogen bonding. [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 present work describes the synthesis of molnupiravir by employing commercially available inexpensive materials in two steps with an overall yield of 85.7%. The synthetic methodology starts with an eco-friendly starting material, that is, cytidine and establishes an alternative way to avoid costly enzyme mediated reactions. This synthetic strategy involves a selective acylation of cytidine as the first key step followed by the second step, that is, hydroxamination reaction. The major advantage of this protocol is that it is completely free of protection and deprotection reactions. Chemoselective acylation of cytidine's primary alcohol was achieved using isobutyryl chloride, Et3N, and DMF solvent (89.3% yield). The aqueous phase transformation was achieved for the hydroxamination reaction with a 96% yield. [ABSTRACT FROM AUTHOR]

To provide a scientific basis for the follow-up resource utilization and food development of Jinzhai hybrid G. elata, the ultra-high performance liquid chromatography coupled with mass spectrometry was utilized to accurately determine the contents of amino acids and nucleosides in Jinzhai Hongwu hybrid Gastrodia elata Bl. and its parents Yunnan G. elata Bl. f. glauca S. Chow and Jinzhai G. elata Bl. f. elata. Statistical methods were also applied to clarify and comprehensively evaluate the composition and content differences in amino acids and nucleosides among the three varieties of G. elata. C18 column (2.1 mm×100 mm, 1.8 μm) was used with 0.2% formic acid water (A)-acetonitrile (B) as the mobile phase at a flow rate of 0.2 mL/min. The column temperature was 30 ℃ with gradient elution. Moreover, electrospray ion source was measured in multiple reaction monitoring (MRM) mode, which was set as spray voltage at 5500 V; ionization temperature at 550 ℃; ion source gas pressure (Gas) at 241.3 kPa, atomizing gas (GS1) at 379.2 kPa, and auxiliary gas (GS2) at 379.2 kPa. The results revealed that there was a good linear relationship in the range of 0~144.58 μg/mL of the 31 components. The coefficient of determination R2 was greater than 0.999, and the RSD of the precision, stability, and repeatability of the peak area was not greater than 3.0%. The average recovery rate was between 92.69% and 99.5%, while recovery rate RSD ranged from 1.3% to 2.9%. Based on all above, G. elata was rich in amino acids and nucleotides, of which glutamic acid and aspartic acid were the main components. The contents of total amino acids and nucleosides in hybrid G. elata were higher than those of its parents G. elata. And there was a significant difference in the amino acids contents of different varieties (P

Background: The nucleoside FF‐10502‐01, structurally similar to but with different biologic effects than gemcitabine, shows promising activity both alone and combined with cisplatin in preclinical gemcitabine‐resistant tumor models. We conducted an open‐label, single‐arm, 3 + 3 first‐in‐human trial to explore the safety, tolerability, and antitumor activity of FF‐10502‐01 in patients with solid tumors. Methods: Patients with inoperable metastatic tumors refractory to standard therapies were enrolled. Escalating intravenous FF‐10502‐01 doses (8–135 mg/m2) were administered weekly for 3 weeks in 28‐day cycles until progressive disease or unacceptable toxicity was observed. Three expansion cohorts were subsequently evaluated. Results: A phase 2 dose of 90 mg/m2 was determined after evaluating 40 patients. Dose‐limiting toxicities included hypotension and nausea. Phase 2a enrolled patients with cholangiocarcinoma (36), gallbladder cancer (10), and pancreatic/other tumors (20). Common adverse events were grade 1–2 rash, pruritus, fever, and fatigue. Grade 3 or 4 hematologic toxicities were observed at low incidences, including thrombocytopenia (5.1%) and neutropenia (2%). Confirmed partial responses (PRs) occurred in five patients with gemcitabine‐refractory tumors, including three with cholangiocarcinoma and one each with gallbladder and urothelial cancer. Median progression‐free and overall survival rates in patients with cholangiocarcinoma were 24.7 and 39.1 weeks, respectively. Prolonged progression‐free survival in patients with cholangiocarcinoma was associated with BAP1 and PBRM1 mutations. Conclusion: FF‐10502‐01 was well tolerated with manageable side effects and limited hematologic toxicity. Durable PRs and disease stabilizations were observed in heavily pretreated biliary tract patients who had received prior gemcitabine. FF‐10502‐01 is distinct from gemcitabine and may represent an effective therapy. A phase 1/2a study of FF‐10502‐01, a nucleoside structurally similar to gemcitabine but with distinct biologic effects, demonstrates activity in patients with gemcitabine‐refractory tumors, including cholangiocarcinoma; this compares favorably to second‐line FOLFOX chemotherapy in patients with advanced biliary cancer. Prolonged progression‐free survival in cholangiocarcinoma was associated with BAP1 and PBRM1 mutations, which may be important for patient selection. [ABSTRACT FROM AUTHOR]

Most naturally occurring nucleotides and nucleosides are N-glycosyl derivatives of β-d-ribose. These N-ribosides are involved in most metabolic processes that occur in cells. They are essential components of nucleic acids, forming the basis for genetic information storage and flow. Moreover, these compounds are involved in numerous catalytic processes, including chemical energy production and storage, in which they serve as cofactors or coribozymes. From a chemical point of view, the overall structure of nucleotides and nucleosides is very similar and simple. However, their unique chemical and structural features render these compounds versatile building blocks that are crucial for life processes in all known organisms. Notably, the universal function of these compounds in encoding genetic information and cellular catalysis strongly suggests their essential role in the origins of life. In this review, we summarize major issues related to the role of N-ribosides in biological systems, especially in the context of the origin of life and its further evolution, through the RNA-based World(s), toward the life we observe today. We also discuss possible reasons why life has arisen from derivatives of β-d-ribofuranose instead of compounds based on other sugar moieties. [ABSTRACT FROM AUTHOR]

Abstract: Migraine is a common disabling disease with a complex pathophysiology. Headache is a frequent side effect after intravenous adenosine administration, although adenosine receptor antagonist, caffeine, relieves migraine headache. These observations suggest a possible involvement of adenosine signaling in headache and migraine pathophysiology. In a randomized, double-blinded, placebo-controlled, crossover study, 18 participants diagnosed with migraine without aura received 120 µg/kg per minute adenosine or placebo over 20 minutes. Headache intensity, migraine-associated symptoms, vital signs, the diameter of the superficial temporal artery (STA), blood flow velocity in the middle cerebral artery (V MCA ), and facial skin blood flow were measured at baseline and every 10 minutes until 2 hours after infusion start. The primary end point was the difference in the incidence of migraine attacks after adenosine infusion compared with placebo. Eighteen participants completed the study. We found no difference in the incidence of migraine after adenosine infusion (7 of 18, 39%) compared with placebo (3 of 18, 17%) ( P = 0.29). Fourteen participants reported headache after adenosine infusion (14 of 18, 78%) compared with placebo (6 of 18, 33%) ( P < 0.01). Adenosine increased heart rate ( P < 0.001), facial skin blood flow ( P < 0.05), and STA diameter (AUC T0-20min , P = 0.01) and decreased V MCA (AUC T0-20min , P < 0.001) compared with placebo. Adenosine induced headache accompanied by a short-lasting (<30 minutes) dilation of intracerebral and extracerebral arteries. The nonsignificant migraine induction might be because of the presence of several adenosine receptors with counteracting signaling, highlighting the need of more selective modulators to dissect the implication of adenosine in migraine. [ABSTRACT FROM AUTHOR]

Boronate affinity materials have been widely studied in separation science, chemical sensing, drug delivery and nanomedicine due to their unique recognition mechanism towards cis-diol-containing biomolecules (cis-diols). In this paper, a new phenylboronic acid (PBA)-functionalized silica particle was prepared by one-pot synthetic strategy based on a PBA-coupled silane reagent, which was synthesized using 1,3,5-benzenetricarboxaldehyde as a spacer arm to covalently link 3-aminophenylboronic acid and 3-aminopropyltriethoxysiliane. Such PBA-functionalized silica particles displayed wrinkle shape with large surface area of 192 m2 g−1, resulting in its high binding capacities of 480 µmol g−1 for catechol and 63 µmol g−1 for adenosine. Moreover, the PBA-functionalized silica particles could rapidly extract the cis-diols in 10 min with a high binding recovery of 83–92%, much higher than its control polymers (1 ~ 47%). In addition to the good extraction performances, the PBA-functionalized silica particles also exhibited fluorescence responses to the cis-diols using two different excitation lights at 300 nm and 470 nm, giving emission lights at 379 nm and 631 nm, respectively, whose fluorescence-responsive mechanism was preliminarily studied. In summary, the developed boronate affinity silica particles can be used not only for the solid-phase extraction of cis-diols, but also to report the recognition events through the fluorescence signals, providing an idea to develop multi-functional boronate affinity materials for simultaneous enrichment and detection of cis-diols in biological samples. [ABSTRACT FROM AUTHOR]

A high-performance liquid chromatography (HPLC) method for the determination of 4 nucleosides by one reference compound in Chinese cordyceps was developed. The sample of Chinese cordyceps was prepared by ultrasonic extraction with a 0.5% phosphoric acid aqueous solution. The separation of the sample was performed on a CORTECS T3 column (100 mm × 4.6 mm, 2.7 μm) by gradient elution with acetonitrile and water at a flow rate of 1.0 mL/min. The wavelengths were set as 258 nm (0-5 min), 252 nm (5-9.1 min), 258 nm (9.1-10.5 min), 249 nm (10.5-20 min) at which 4 nucleosides exhibited identical ultraviolet absorption. The accuracy, precision, reproducibility, and stability tests of the HPLC method were carried out, and the results indicated that the established HPLC method was suitable for the quantitative analysis of 4 nucleosides in Chinese cordyceps. This approach was compared to the traditional external standard method with 4 nucleoside reference compounds and the relative standard errors of the content determination results by the 2 methods were less than 3.5%. The HPLC method developed for quantitative measurement of 4 nucleosides in Chinese cordyceps is simple, lower cost, and time-saving, which provides a methodology alternative for quality control of Chinese cordyceps. [ABSTRACT FROM AUTHOR]

The quality of fish freshness plays a crucial role in the acceptance of consumers and human health. Considering that food safety has recently become a major concern on a global scale, establishing and evaluating fish freshness is crucial for research and development. Some methods that can be used to assess fish freshness are the K-values and the Ki index. Those methods evaluate the fish freshness based on the degradation of nucleosides in fish that occurred during the deterioration process. This study aimed to assess quality freshness (Ki index) in Bombay duck (Harpodon nehereus), one of the tropical fisheries products, using concentration nucleosides in chilling temperature storage conditions for 12 days. Analysis of nucleosides in this study was conducted using a 1 H-NMR (Nuclear Magnetic Resonance) metabolomics approach. Four nucleosides (Inosine, Hypoxanthine, inosine 5' monophosphate, and ATP) were successfully analyzed during this study. This study showed Hypoxanthine was slightly fluctuated, IMP Increased until 4 days then decreased markedly, ATP decreased markedly up to 6 days, then relatively stagnant in the remaining storage and inosine decreased up to 4 days, significantly increased from 6 days until 12 storage. Furthermore, freshness calculation showed that the Ki index of Bombay duck fish significantly increased during chilling storage conditions from 0 days to six days (47% - 94%). Furthermore, the Ki index showed a stable pattern from 6 – 12 days of storage (94% - 95%). The Ki index of Bombay duck value exceeded 80% after storing the fish for four days. Therefore, based on these calculations after 4 days storage in the chilling temperature Bombay ducks is categorized as the fish which is not fresh anymore.

In this article, we present the synthesis and the optical properties of three original molecules as potential fluorescent ribonucleoside analogues incorporating a 1,6-naphthyridin-7(6H)-one scaffold as a fluorescent nucleobase and a 1,2,3-triazole as a linkage. The nucleosides were prepared via a Cu alkyne-azide cycloaddition (CuAAC) reaction between a ribofuranosyl azide and a 4-ethynylpyridine partner. Construction of substituted 1,6-naphthyridin-7(6H)-ones was achieved through two additional steps. Optical property studies were investigated on nucleoside analogues. Powerful fluorescence properties have been evidenced with a remarkable change of emissivity depending on the polarity of the solvent, making these molecules suitable as a new class of artificial fluorescent nucleosides for investigating enzyme binding sites as well as probing nucleic acids. In addition, we are convinced that such analogues could be of great interest in the search for new antiviral or antitumoral drugs based on nucleosides.

Tissue defects can lead to serious health problems and often require grafts or transplants to repair damaged soft tissues. However, these procedures can be complex and may not always be feasible due to a lack of available tissue. Hydrogels have shown potential as a replacement for tissue grafts due to their ability to support cell survival and encapsulate biomolecules such as growth factors. In particular, guanosine-based hydrogels have been explored as a potential solution, but they often exhibit limited stability which hampers their use in the biofabrication of complex grafts. To address this issue, we explored the use of borate ester chemistry and more complex boric acid derivatives to improve the stability and properties of guanosine-based hydrogels. We hypothesized that the aromatic rings in these derivatives would enhance the stability and printability of the hydrogels through added π-π stack interactions. After optimization, 13 compositions containing either 2-naphthylboronic acid or boric acid were selected. Morphology studies shows a well-defined nanofibrilar structure with good printable properties (thixotropic behaviour, print fidelity and printability). Moreover, the pH of all tested hydrogels was within the range suitable for cell viability (7.4–8.3). Nevertheless, only the boric acid-based formulations were stable for at least 7 days. Thus, our results clearly demonstrated that the presence of additional aromatic rings did actually impair the hydrogel properties. We speculate that this is due to steric hindrance caused by adjacent groups, which disrupt the correct orientation of the aromatic groups required for effective π-π stack interactions of the guanosine building block. Despite this drawback, the developed guanosine-boric acid hydrogel exhibited good thixotropic properties and was able to support cell survival, proliferation, and migration. For instance, SaOS-2 cells planted on these printed structures readily migrated into the hydrogel and showed nearly 100% cell viability after 7 days. In conclusion, our findings highlight the potential of guanosine-boric acid hydrogels as tissue engineering scaffolds that can be readily enhanced with living cells and bioactive molecules. Thus, our work represents a significant advancement towards the development of functionalized guanosine-based hydrogels.

Water‐soluble π‐conjugated polyfluorene bearing 6‐N1‐cytosinehexyl and 6‐trimethylammoniumhexyl bromide side chains, namely polymer‐1, was synthesized by Suzuki polycondensation. The absorption onset wavelength (λonset) of the polymer was longer than that of the monomer and confirmed the presence of the π‐conjugated system along the polymer chain. The cyclic voltammetry and UV–vis analyses showed that the highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels of the polymer were −5.5 and −2.6 eV, respectively. The photoluminescence (PL) intensity of the polymer decreased with increasing DNA chain length (m) upon adding (TTAGGG)m (T = thymine, A = adenine, and G = guanine; m = 2, 4, 6, and 8), indicating that the polymer could detect telomere DNA chain lengths with higher precision than previously reported DNA sensors. Similarly, the PL intensity decreased with the addition of nucleosides. Photoinduced charge transfer in the complex between the polymer and DNA or nucleoside played an important role in the PL response of the polymer toward analytes. The sensing behavior was analyzed using the Stern–Volmer and Benesi–Hildebrand methods. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: An efficient and practical synthesis of heterocyclic nucleosides is developed by a catalyst‐free highly regioselective and diastereoselective [3+2] annulation of α‐purine‐substituted acrylates with nitrones. The reaction operates with excellent functional group tolerance, very mild reaction conditions, and with the green, sustainable, and eco‐friendly 2‐methyltetrahydrofuran (2‐MeTHF) as solvent. Compared with other reactions of electron‐deficient olefin dipolarophiles with nitrones, different regioselective cycloaddition products were observed in this work. This 1,3‐dipolar cycloaddition reaction gives a series of isoxazolidinyl nucleosides in good to excellent yields with promising applications in biochemistry and medicinal chemistry. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: An efficient and practical synthesis of heterocyclic nucleosides is developed by a catalyst‐free highly regioselective and diastereoselective [3+2] annulation of α‐purine‐substituted acrylates with nitrones. The reaction operates with excellent functional group tolerance, very mild reaction conditions, and with the green, sustainable, and eco‐friendly 2‐methyltetrahydrofuran (2‐MeTHF) as solvent. Compared with other reactions of electron‐deficient olefin dipolarophiles with nitrones, different regioselective cycloaddition products were observed in this work. This 1,3‐dipolar cycloaddition reaction gives a series of isoxazolidinyl nucleosides in good to excellent yields with promising applications in biochemistry and medicinal chemistry. [ABSTRACT FROM AUTHOR]

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ωoxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates. [ABSTRACT FROM AUTHOR]

Herein, we report a practical method for de novo preparation of imino‐d‐ribitol and C‐azanucleosides. The diastereopure Imino‐d‐ribitol was synthesized on a multigram scale by simple manipulation, and late‐stage anomeric derivatization by regio‐ and diastereoselective electrochemical C(sp3)−H activation enabled the efficient synthesis of the corresponding C‐azanucleosides with high β‐selectivity. [ABSTRACT FROM AUTHOR]

Winter melon fruits were grown in the field using anaerobic soil disinfestation (ASD) and conventional fertilizer alone as the control treatment. Fruits were harvested and stored at 20 °C for 120 d, the juice was processed on day one and day 120, and the effects of soil amendment and 120 d storage on the juice's physical and chemical (sugars, acids, volatile and nutritional compounds) properties were evaluated. Fruit juice extracted from ASD-grown fruit had greater magnitude of zeta potential than the control juice, indicating it was physically more stable than the juice obtained from the control conditions. ASD fruit juice had lower soluble solids content (SSC), and lower volatile compounds that contribute green, grass, and sulfur notes, and negatively influence flavor quality. ASD fruit juice had higher vitamin B5 and cytidine. Juice processed from 120 d stored fruit had less yield due to 12.4–15.6% weight loss. The non-soluble solids content was higher and particle size was larger, and the SSC and individual sugars decreased. However, titratable acidity (TA) increased primarily due to increased citric acid. Out of 16 free amino acids, 6 increased and only 1 decreased. However, three out of five nucleosides decreased; vitamins B1 and B6 increased; vitamins B2, B3 and C decreased. Overall, juice derived from fruit produced using ASD was physically more stable and had less SSC and off-odor volatiles than the control, while the fruit juice of those stored for 120 d had lower SSC and higher TA and nutritional profiles, comparable to freshly harvested fruit. [ABSTRACT FROM AUTHOR]

Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host–guest complexes with β-cyclodextrin (β-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with β-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of β-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the β-CD cavity. [ABSTRACT FROM AUTHOR]

Nucleosides represent one of the key building blocks of biochemistry. There is significant interest in the synthesis of nucleoside‐derived materials for applications as probes, biochemical models, and pharmaceuticals. Palladium‐catalyzed cross‐coupling reactions are effective methods for making covalent modification of carbon and nitrogen sites on nucleobases under mild conditions. Water‐soluble catalysts derived from palladium and hydrophilic ligands, such as tris(3‐sulfonatophenyl)phosphine trisodium (TPPTS), are efficient catalysts for a range of coupling reactions of unprotected halonucleosides. Over the past two decades, these methods have been extended to direct functionalization of halonucleotides, as well as RNA and DNA oligonucleotides (ONs) containing halogenated bases. These methods can be run under biocompatible conditions, including examples of Suzuki coupling of modified DNA in whole cells and tissue samples. In this account, development of this methodology by our group and others is highlighted along with the extension of these catalyst systems to modification of nucleotides and ONs. [ABSTRACT FROM AUTHOR]

Nucleoside reverse transcriptase inhibitors are the first class of drugs to be approved by the FDA for the suppression of HIV-1 and are widely used for this purpose in combination with drugs of other classes. Despite the progress in HIV-1 treatment, there is still the need to develop novel efficient antivirals. Here the efficiency of HIV-1 inhibition by a set of original 5-substituted uridine nucleosides was studied. We used the replication deficient human immunodeficiency virus (HIV-1)-based lentiviral particles and identified that among the studied compounds, 2′,3′-isopropylidene-5-iodouridine was shown to cause anti-HIV-1 activity. Importantly, no toxic action of this compound against the cells of T-cell origin was found. We determined that this compound is significantly more efficient at suppressing HIV-1 compared to Azidothymidine (AZT) when taken at the high non-toxic concentrations. We did not find any profit when using AZT in combination with 2′,3′-isopropylidene-5-iodouridine. 2′,3′-Isopropylidene-5-iodouridine acts synergistically to repress HIV-1 when combined with the CDK4/6 inhibitor Palbociclib in low non-toxic concentration. No synergistic antiviral action was detected when AZT was combined with Palbociclib. We suggest 2′,3′-isopropylidene-5-iodouridine as a novel perspective non-toxic compound that may be used for HIV-l suppression.

Samuel J Bunu, Azibanasamesa DC Owaba, Edebi N Vaikosen, Benjamin U Ebeshi Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, Niger Delta University, Wilberforce Island, Bayelsa State, NigeriaCorrespondence: Samuel J Bunu Tel +2348069703966Email Pharmsamuelbunu@gmail.comPurpose: DNA polymorphism describes the difference between individuals, groups, or ethnicities, races, etc., in terms of their DNA sequences or phenotypes as relates to drug metabolism. Using predictive genotyping of drug-metabolizing genes, we can develop individuals’ drug therapies that are less toxic and more effective. The main aim of the study was to evaluate genotype–phenotype-based correlation and incidence of genetic polymorphism of efavirenz blood levels among HIV/AIDS patients of the Niger Delta population.Methods: A study questionnaire was designed to obtained patients’ data, blood samples were obtained, plasma was separated from the serum using a centrifuge for 5 minutes at 4000 rpm for HPLC analysis, polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis was conducted using Bsrl endonuclease enzyme to digest the PCR amplicons. Standard efavirenz was used at 0.5, 1, 2, 4, 16 mg/L to construct a calibration curve. Data were analyzed with SPSS software using chi-square test at p-value ≤ 0.5 and Microsoft excel 2013, while PCR and RFLP results were obtained after 1% Agarose gel electrophoresis, respectively.Results: Phenotypic results showed that the participants had different efavirenz plasma concentrations. Six subjects (12%) had efavirenz plasma levels below 0.10 mg/L, considered ultra-rapid metabolizers (UMs), 22 (44%) 0.10 mg/L to 0.90 mg/L, classified as extensive metabolizers (EMs), 19 (38%) had 1.0 to 3.9 mg/L and were noted as intermediate metabolizers (IM), while 3 (6%) subjects showed efavirenz plasma levels from 4.0 mg/L to 6.0 mg/L, categorized as poor metabolizers (PM). RFLP results showed more than half of the population (56%) with a homozygous wild-type gene with CYP2B6&ast;1&ast;1 allele, 38% were CYP2B6&ast;1&ast;6 (heterozygous mutant) allele and 6% had homozygous mutant gene (CYP2B6&ast;6&ast;6 allele). Out of the 15 male subjects among the 50 patients that participated in the study, 8% were UM, 12% EM, 14% IM while no PM was observed, on the contrary, out of the 35 females participated in the study, 4% were observed as UM, 32% EM, 24% IM, while 6% were PM.Conclusion: There was no significant difference (p ≤ 0.05) between genotype and phenotype data for CYP2B6 polymorphism, among the HIV/AIDS patients that participated in this study. Genetic polymorphism of the CYP2B6 gene is prevalent among HIV/AIDs patients in the Niger Delta ethnic population on efavirenz-based HAART treatment, as the population having homozygous mutant gene or PM are > 1% (6%).Keywords: Antiretroviral, NNRTIs, CYP2B6, Genetic polymorphism, efavirenz, phenotype

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ω-oxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates.

We isolated and purified aromatic compounds from water extracts of Grifola gargal and elucidated their structures by instrumental analysis. The results revealed that adenosine was one of the aromatic compounds in the extracts. Moreover, nucleosides (cytidine, uridine, guanosine, and thymidine) in the water extracts from Grifola gargal were identified by high-performance liquid chromatography (HPLC). In addition, the nucleoside contents of water extracts of 17 mushroom species were also identified by HPLC, and their quantitative values were determined by principal component analysis. Pleurotus ostreatus had the highest adenosine content among the tested mushrooms and different mushrooms had different amounts of nucleosides. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is an emerging global pandemic with severe morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molnupiravir, an ester prodrug form of N4-hydroxycytidine (NHC), was recently emergency-use approved for the treatment of early SARS-CoV-2 infections. Herein, we report the synthesis and evaluation of a series of novel NHC analogs. [ABSTRACT FROM AUTHOR]