Sugar Moiety Research Articles

Red Blood Cells Oligosaccharides as Targets for Plasmodium Invasion.

The key element in developing a successful malaria treatment is a good understanding of molecular mechanisms engaged in human host infection. It is assumed that oligosaccharides play a significant role in Plasmodium parasites binding to RBCs at different steps of host infection. The formation of a tight junction between EBL merozoite ligands and glycophorin receptors is the crucial interaction in ensuring merozoite entry into RBCs. It was proposed that sialic acid residues of O/N-linked glycans form clusters on a human glycophorins polypeptide chain, which facilitates the binding. Therefore, specific carbohydrate drugs have been suggested as possible malaria treatments. It was shown that the sugar moieties of N-acetylneuraminyl-N-acetate-lactosamine and 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA), which is its structural analog, can inhibit P. falciparum EBA-175-GPA interaction. Moreover, heparin-like molecules might be used as antimalarial drugs with some modifications to overcome their anticoagulant properties. Assuming that the principal interactions of Plasmodium merozoites and host cells are mediated by carbohydrates or glycan moieties, glycobiology-based approaches may lead to new malaria therapeutic targets.

Structural Insights into Amelioration Effects of Quercetin and Its Glycoside Derivatives on NAFLD in Mice by Modulating the Gut Microbiota and Host Metabolism.

The sugar moieties of natural flavonoids determine their absorption, bioavailability, and bioactivity in humans. To explore structure-dependent bioactivities of quercetin, isoquercetin, and rutin, which have the same basic skeleton linking different sugar moieties, we systemically investigated the ameliorative effects of dietary these flavonoids on high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) of mice. Our results revealed that isoquercetin exhibits the strongest capability in improving NAFLD phenotypes of mice, including body and liver weight gain, glucose intolerance, and systemic inflammation in comparison with quercetin and rutin. At the molecular level, dietary isoquercetin markedly ameliorated liver dysfunction and host metabolic disorders in mice with NAFLD. At the microbial level, the three flavonoids compounds, especially isoquercetin, can effectively regulate the gut microbiota composition, such as genera Akkermansia, Bifidobacterium, and Lactobacillus, which were significantly disrupted in NAFLD mice. These comparative findings offer new insights into the structure-dependent activities of natural flavonoids for NAFLD treatment.

Lead identification of novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid derivative as a potent heparanase-1 inhibitor

Heparanase-1 (HPSE1) is an endo-β-d-glucuronidase that cleaves heparan sulfate proteoglycans into short-chain heparan sulfates (HS). The inhibition of HPSE1 has therapeutic potential for proteinuric diseases such as nephrotic syndrome because increased HPSE1 expression is associated with the loss of HS in the glomerular basement membrane, leading to the development of proteinuria. The present study examined the generation of a lead compound focusing on chemical structures with a sugar moiety, such as glycosides and sugar analogs, taking their physical properties into consideration. Compound 10, an exo-β-d-glucuronidase (GUSβ) inhibitor, was found to have a weak inhibitory activity against endo-β-d-glucuronidase HPSE1. A structure–activity relationship study using the X-ray co-crystal structure of 10 and HPSE1 resulted in 12a, which showed a more than 14-fold increase in HPSE1 inhibitory activity compared with that of 10. Compound 12a could be a novel lead compound for the development of a potent HPSE1 inhibitor.

Chemo-enzymatic Synthesis of Pseudo-trisaccharide Aminoglycoside Antibiotics with Enhanced Nonsense Read-through Inducer Activity.

Aminoglycosides (AGs) are broad-spectrum antibiotics used to treat bacterial infections. Over the last two decades, studies have reported the potential of AGs in the treatment of genetic disorders caused by nonsense mutations, owing to their ability to induce the ribosomes to read through these mutations and produce a full-length protein. However, the principal limitation in the clinical application of AGs arises from their high toxicity, including nephrotoxicity and ototoxicity. In this study, five novel pseudo-trisaccharide analogs were synthesized by chemo-enzymatic synthesis by acid hydrolysis of commercially available AGs, followed by an enzymatic reaction using recombinant substrate-flexible KanM2 glycosyltransferase. The relationships between their structures and biological activities, including the antibacterial, nephrotoxic, and nonsense readthrough inducer (NRI) activities, were investigated. The absence of 1-N-acylation, 3',4'-dideoxygenation, and post-glycosyl transfer modifications on the third sugar moiety of AGs diminishes their antibacterial activities. The 3',4'-dihydroxy and 6'-hydroxy moieties regulate the in vitro nephrotoxicity of AGs in mammalian cell lines. The 3',4'-dihydroxy and 6'-methyl scaffolds are indispensable for the ex vivo NRI activity of AGs. Based on the alleviated in vitro antibacterial properties and nephrotoxicity, and the highest ex vivo NRI activity among the five compounds, a kanamycin analog (6'-methyl-3''-deamino-3''-hydroxykanamycin C) was selected as a novel AG hit for further studies on human genetic disorders caused by premature transcriptional termination.

Amphiphilic Sugar Derivatives Linked with Gallic Acid Bearing Tris-alkoxy Groups throughL-Lysine Linkage: Self-assembly and Efficient Dye Removal in Water-organic Solvent Biphasic System

Amphiphilic small molecules (1), constructed from two sugar moieties and a gallic acid bearing tris-alkoxy group via an L-lysine linkage, were synthesized. Amphiphile (1a) exhibited fibrous self-assembly through emulsification in a water-organic solvent biphasic system and showed efficient removal of various organic dyes with varying degrees of hydrophobicity from the aqueous phase.

Molecular insights into the mechanism of sugar-modified enkephalin binding to opioid receptors

Opioid receptors (delta, kappa, and mu) belong to the G protein-coupled receptor (GPCR) superfamily. They are responsible for pain perception - being activated by opioid peptides such as enkephalins, endorphins and dynorphins and by opiates, such as morphine. Enkephalins are naturally occurring endogenous pentapeptides with the amino acid sequence Tyr-Gly-Gly-Phe-Leu/Met. Both enkephalins are potent agonists of the delta receptor, and to a lesser extent the mu receptor, with little to no effect on the kappa receptor. Like most small peptides, enkephalins are easily catabolised via enzymatic degradation and show poor blood-brain barrier penetration. The attachment of sugars to peptides increases their penetration of the blood-brain barrier but also may affect interactions with receptors. In this study, the [Leu5]enkephalin and [Leu5]enkephalin containing the β-D-glucuronic acid were investigated to explain how the presence of sugar moiety in the peptide molecule influences its interaction with the opioid receptors. In conclusion, the conjugation of an enkephalin molecule with the glucuronic acid has a direct and strong impact on the receptor-ligand interactions. The enhancement of ligand binding is much stronger in the delta receptor than in the mu receptor; thus, enkephalin conjugated with glucuronic acid shows greater selectivity toward the delta opioid receptor than the original peptide.

Discovery, Development and Design of Anthocyanins-Inspired Anticancer Agents: A Comprehensive Review.

Mother Nature is an indispensable source of bioactive natural products. Bioactive secondary metabolites have played a crucial role in the drug development and discovery process; mainly, anticancer and antibiotic molecules are extensively enriched with molecules of natural origin. Anthocyanins are water-soluble secondary metabolites found in most species in the plant domain, especially flowers, fruits, and tubers. These natural vacuolar pigments belong to the chemical class of phenolic moieties, which are responsible for the shiny orange, red, blue, pink, and violet colors in the fruits, flowers, and vegetables. Chemically, anthocyanins comprise a core structure in the form of flavylium cation or 2-phenylbenzopyrylium, and these natural colorants are polyhydroxy and polymethoxy analouges of this flavylium cation and can have sugar moieties or acylated groups linked at different positions. Currently, these molecules have raised a growing interest because of their wide range of colors, innocuous and beneficial health effects, and commercial application in functional foods, nutraceuticals, pharmaceutical and cosmetic industries. However, interest in anthocyanin derivatives has noticeably enhanced in recent years due to their higher stability, improved bioavailability in biological matrices, and better use in food matrices and cosmetic products. Due to the enormous potential of natural anthocyanins and their derivatives, this review tries to cover syntheses of anthocyanins and their analogues, chemical derivatization of anthocyanins, and anticancer activities, such as breast, colorectal, leukemia, lung, prostate, and skin cancer of anthocyanins efficiently.

Assessment of bacterial biosurfactant production and application in Enhanced Oil Recovery (EOR)—A green approach

The present work attempts to investigate production of biosurfactant, in a modified synthetic media, by less explored bacterial strain isolated from iron factory waste effluent from West Bengal, India and its application in enhanced oil recovery operations. The screened isolate was identified to be Pseudomonas mendocina by 16s rDNA gene homology (NCBI-Genebank accession no. MH091331). It showed a high emulsification of 68.3 ± 2.86%, lowering surface tension of water to 31 mN/ m and CMC of 125 mg l −1 and found to be alkalophillic (pH 6 to 12) and halophilic (up to 6% NaCl) in nature. Batch study in optimized media led to maximum yield of 3.09 ± 0.12 g l −1 . Production kinetic analysis by Luedeking Piret model successfully predicted mixed growth associated biosurfactant production with α and β values of 0.73 and 1.60 respectively and a yield coefficient of 0.82. Cost estimation for production of biosurfactant was calculated under lab scale conditions. Characterization of the extracted biosurfactant by anthrone test and Lowry’s protein estimation, TLC, FTIR, H 1 NMR and FESEM revealed the presence of sugar, peptides and lipid moieties. The biosurfactant obtained is extremely robust with high stability, sustaining wide range of pH (4 to 12), salinity (0.5 to 10% NaCl) and temperature (up to 100 °C). Toxicity assessment by Vigna radiata seed bioassay and MTT assay using and HEK293 cell line showed the non-toxic nature of the biosurfactant. Crude biosurfactant could play effective role in oil recovery with 44.3 ± 0.5 % enhanced oil recovery using sand packed column. • Biosurfactant (BS) from newly isolated halo-alkalophillic bacterial strain. • BS production in economically suitable optimized media. • Notably stable BS, tolerating extreme physiological conditions. • BS exhibiting presence of both glycolipids and lipopeptides: blend nature. • Potential use of crude biosurfactant for enhanced oil recovery.

Prediction and Motif Analysis of 2’-O-methylation Using a Hybrid Deep Learning Model from RNA Primary Sequence and Nanopore Signals

Background: 2’-O-Methylation (2’-O-Me) is a post-transcriptional RNA modification that occurs in the ribose sugar moiety of all four nucleotides and is abundant in both coding and non-coding RNAs. Accurate prediction of each subtype of 2’-O-Me (Am, Cm, Gm, Um) helps understand their role in RNA metabolism and function. Objective: This study aims to build models that can predict each subtype of 2’-O-Me from RNA sequence and nanopore signals and exploit the model interpretability for sequence motif mining. Methods: We first propose a novel deep learning model DeepNm to better capture the sequence features of each subtype with a multi-scale framework. Based on DeepNm, we continue to propose HybridNm, which combines sequences and nanopore signals through a dual-path framework. The nanopore signalderived features are first passed through a convolutional layer and then merged with sequence features extracted from different scales for final classification. Results: A 5-fold cross-validation process on Nm-seq data shows that DeepNm outperforms two stateof- the-art 2’-O-Me predictors. After incorporating nanopore signal-derived features, HybridNm further achieved significant improvements. Through model interpretation, we identified not only subtypespecific motifs but also revealed shared motifs between subtypes. In addition, Cm, Gm, and Um shared motifs with the well-studied m6A RNA methylation, suggesting a potential interplay among different RNA modifications and the complex nature of epitranscriptome regulation. Conclusion: The proposed frameworks can be useful tools to predict 2’-O-Me subtypes accurately and reveal specific sequence patterns.

Glycopolymer and Poly(β-amino ester)-Based Amphiphilic Block Copolymer as a Drug Carrier.

Glycopolymers are synthetic macromolecules having pendant sugar moieties and widely utilized to target cancer cells. They are usually considered as a hydrophilic segment of amphiphilic block copolymers to fabricate micelles as drug carriers. A novel amphiphilic block copolymer, namely, poly(2-deoxy-2-methacrylamido-d-glucose-co-2-hydroxyethyl methacrylate)-b-poly(β-amino ester) [P(MAG-co-HEMA)-b-PBAE], with active cancer cell targeting potential and pH responsivity was prepared. Tetrazine end functional P(MAG-co-HEMA) and norbornene end functional PBAE blocks were separately synthesized through reversible addition fragmentation chain transfer polymerization and Michael addition-based poly-condensation, respectively, and followed by end-group transformation. Then, inverse electron demand Diels Alder reaction between the tetrazine and the norbornene groups was performed by simply mixing to obtain the amphiphilic block copolymer. After characterization of the block copolymer in terms of chemical structure, pH responsivity, and drug loading/releasing, pH-responsive micelles were obtained with or without doxorubicin (DOX), a model anticancer drug. The micelles exhibited a sharp protonated/deprotonated transition on tertiary amine groups around pH 6.75 and the pH-specific release of DOX below this value. Eventually, the drug delivery potential was evaluated by cytotoxicity assays on both the noncancerous human umbilical vein endothelial cell (HUVEC) cell line and glioblastoma cell line, U87-MG. While the DOX-loaded polymeric micelles were not toxic in noncancerous HUVEC cells, being toxic only to the cancer cells indicates that it is a potential specific cell targeting strategy in the treatment of cancer.

Verniciflavanol A, a profisetinidin-type-4-arylflavan-3-ol from toxicodendron vernicifluum protects SH-SY5Y cells against H2O2-Induced oxidative stress

Eleven undescribed derivatives of flavan, including flavan-3,4-diols vernicinosides A-H and profisetinidin-type-4-arylflavan-3-ols verniciflavanols A-C, together with eight known compounds were purified from the heartwood of Toxicodendron vernicifluum. The chemical structures of the undescribed compounds were characterized by spectroscopic data interpretation, including NMR (1H and 13C NMR HSQC and HMBC) and HRESIMS analysis. CD data analysis was conducted to assign the absolute configurations of the undescribed compounds and the active compound verniciflavanol A was also confirmed by ECD experiment. The absolute configuration of the sugar moiety was identified by GC analysis of chiral derivatives in the hydrolysate. MTT assay was applied to test these compounds against H2O2-induced oxidative stress in human neuroblastoma SH-SY5Y cells. Results found that verniciflavanol A demonstrated the best potential in protecting SH-SY5Y cells against H2O2-induced oxidative stress by inhibiting cell apoptosis and attenuate reactive oxygen species (ROS) level and mitochondrial dysfunction. And the underlying mechanism was confirmed to be associated with Nrf2-antioxidant response element signaling and IL-6 cell survival pathways.

Spectroscopic characterization of different protonation/deprotonation states of Barbaloin in aqueous solution

Barbaloin (10–glucopyranosyl–1,8–dihydroxy–3–(hydroxymethyl)–9(10H)–anthraquinone: aloin A), present in Aloe species, is widely used in food, cosmetic and pharmaceutical industries. Here we characterize its optical absorption and emission spectra in aqueous solution at different pH values. Through pH titration, using both absorption and fluorescence spectroscopy, two pKa values for Barbaloin were determined: pKa1=9.6±0.6 and pKa2=12.6±0.8. These acidity constants were found to be higher than those found for Emodin, a similar molecule which lacks the sugar moiety present in Barbaloin. Performing quantum mechanical calculations for non-ionized, singly, doubly, and triply deprotonated forms of Barbaloin in vacuum and in water, we assigned the positions of the site for the first and third deprotonation in the anthraquinone group, and the second deprotonation in the glucose group. The instability of Barbaloin in high pH solutions is discussed here, and the optical absorption and fluorescence spectra due to products resulted from Barbaloin degradation at high pH is well separated from the Barbaloin original spectra. Biological fluids have specific pH values to maintain homeostasis, hence determining the pKa of Barbaloin is important to evaluate the mechanism of action of this drug in different parts of an organism as well as to predict pharmacological relevant parameters, such as absorption, distribution, metabolism, and excretion.

Astersaponin I from Aster koraiensis is a natural viral fusion blocker that inhibits the infection of SARS-CoV-2 variants and syncytium formation

The continuous emergence of SARS-CoV-2 variants prolongs COVID-19 pandemic. Although SARS-CoV-2 vaccines and therapeutics are currently available, there is still a need for development of safe and effective drugs against SARS-CoV-2 and also for preparedness for the next pandemic. Here, we discover that astersaponin I (AI), a triterpenoid saponin in Aster koraiensis inhibits SARS-CoV-2 entry pathways at the plasma membrane and within the endosomal compartments mainly by increasing cholesterol content in the plasma membrane and interfering with the fusion of SARS-CoV-2 envelope with the host cell membrane. Moreover, we find that this functional property of AI as a fusion blocker enables it to inhibit the infection with SARS-CoV-2 variants including the Alpha, Beta, Delta, and Omicron with a similar efficacy, and the formation of syncytium, a multinucleated cells driven by SARS-CoV-2 spike protein-mediated cell-to-cell fusion. Finally, we claim that the triterpene backbone as well as the attached hydrophilic sugar moieties of AI are structurally important for its inhibitory activity against the membrane fusion event. Overall, this study demonstrates that AI is a natural viral fusion inhibitor and proposes that it can be a broad-spectrum antiviral agent against current COVID-19 pandemic and future outbreaks of novel viral pathogens.

The Norsesquiterpene Glycoside Ptaquiloside as a Poisonous, Carcinogenic Component of Certain Ferns

Previous studies related to the ptaquiloside molecule, a carcinogenic secondary metabolite known from the world of ferns, are summarised. Ptaquiloside (PTA) belongs to the group of norsesquiterpenes of the illudane type. The name illudane refers to the fungal taxa from which the first representatives of the molecular group were identified. Ptaquiloside occurs mainly in Pteridium fern species, although it is also known in other fern taxa. The species of the genus Pteridium are common, frequent invasive species on all continents, and PTA is formed in smaller or larger amounts in all organs of the affected species. The effects of PTA and of their derivatives on animals and humans are of great toxicological significance. Its basic chemical property is that the molecule can be transformed. First, with the loss of sugar moiety, ptaquilosine is formed, and then, under certain conditions, a dienone derivative (pteridienone) may arise. The latter can alkylate (through its cyclopropane groups) certain molecules, including DNA, in animal or human organisms. In this case, DNA adducts are formed, which can later have a carcinogenic effect through point mutations. The scope of the PTA is interdisciplinary in nature since, for example, molecules from plant biomass can enter the body of animals or humans in several ways (directly and indirectly). Due to its physico-chemical properties (excellent water solubility), PTA can get from the plant into the soil and then into different water layers. PTA molecules that enter the soil, but mainly water, undergo degradation (hydrolytic) processes, so it is very important to clarify the toxicological conditions of a given ecosystem and to estimate the possible risks caused by PTA. The toxicoses and diseases of the animal world (mainly for ruminant farm animals) caused by PTA are briefly described. The intake of PTA-containing plants as a feed source causes not only various syndromes but can also enter the milk (and meat) of animals. In connection with the toxicological safety of the food chain, it is important to investigate the transport of carcinogenic PTA metabolites between organisms in a reassuring manner and in detail. This is a global, interdisciplinary task. The present review aims to contribute to this.

Designing benign molecules: The influence of O-acetylated glucosamine-substituents on the environmental biodegradability of fluoroquinolones

Antibiotics are detected worldwide in the aquatic environment, with continuously rising concentrations. Antibiotics in the environment have the potential to damage ecosystems and contribute to the development of resistance. Whilst a few antibiotics, such as some β-lactams, are eliminated by effluent treatment, others, such as fluoroquinolones, are not or just partially removed and enter the environment. Therefore, approaches are needed to tackle those problems at the compound level. Benign by design (BbD), an important part of green pharmacy, has the goal to integrate environmental fate and end-of-use considerations at the very beginning, i.e., into the design of active pharmaceutical ingredients. Hence, pharmaceuticals should be designed to be sufficiently active and stable during storage and usage but should degrade after excretion into the environment, so that they cannot cause any adverse effects.Fluoroquinolones (FQs) are important broad-spectrum antibiotics. They are known to be persistent in the environment and to be neither inactivated nor degraded or even mineralized during sewage treatment. The addition of new substituents via amidation, like glucosamine moieties, at the carboxylic group of FQs, led to better antimicrobial activity compared to its parent compounds against various microorganisms. To investigate if the addition of sugar moieties could improve the overall environmental biodegradability of FQs, eight novel quinolone and fluoroquinolone analogs conjugated with 1,3,4,6-Tetra-O-acetyl-β-d-glucosamine and 2-deoxy-d-glucopyranose have been investigated regarding their ready biodegradability (OECD 301D/F) and their degradation pathways have been analyzed. According to the OECD 301D test, none of the substances could be classified as readily biodegradable. However, the O-acetyl analogs did undergo a partial degradation of the O-acetyl glucosamine moiety, via stepwise deacetylation and the degradation of the whole glucosamine moiety. The degradation resulted in Fluoroquinolone-3-carboxamide derivatives.Those insights could be further used as input for fragment-based design of benign APIs that will degrade once they reached the environment.

Synthesis and Biological Evaluation of Cardiac Glycosides for Cancer Therapy by Targeting the DNA Damage Response.

Cardiac glycosides (CGs) are bioactive compounds originally used to treat heart diseases, but recent studies have demonstrated their anticancer activity. We previously demonstrated that Antiaris toxicaria 2 (AT2) possesses anticancer activity in KRAS mutated lung cancers via impinging on the DNA damage response (DDR) pathway. Toward developing this class of molecules for cancer therapy, herein we report a multistep synthetic route utilizing k-strophanthidin as the initial building block for determination of structure-activity relationships (SARs). A systematic structural design approach was applied that included modifications of the sugar moiety, the glycoside linker, stereochemistry, and lactone ring substitutions to generate a library of O-glycosides and MeON-neoglycosides derivatives. These molecules were screened for their anticancer activities and their impact on DDR signaling in KRAS mutant lung cancer cells. These results demonstrate the ability to chemically synthesize CG derivatives and define the SARs to optimize AT2 as a cancer therapeutic.

Automated synthesizer strings together 1,080 sugar moieties

Automated synthesizer strings together 1,080 sugar moieties

Intermolecular copigmentation between anthocyanidin-3,5-O-diglucosides and three phenolic compounds: Insights from experimental and theoretical studies

Anthocyanidin-3,5-O-diglucosides are the main pigments in red wines made from non-vinifera and hybrid species. In this work, intermolecular copigmentation between three common anthocyanidin-3,5-O-diglucosides and three types of phenolic copigments was systematically investigated in model wine solutions through experimental and theoretical methods. The impact of the sugar moiety at the C5 position of anthocyanin A ring was studied emphatically. Results showed that the anthocyanidin-3,5-O-diglucosides produced much stronger hyperchromic effects compared to the anthocyanidin-3-O-glucosides. Thermodynamic analysis and theoretical calculations suggested higher affinity of the anthocyanidin-3,5-O-diglucosides towards copigments (larger K values and lower ∆G) than corresponding monoglucosidic anthocyanins, mainly due to the enhancement of hydrogen bonds and van der Waals forces resulting from the additional glucose. In conclusion, the results revealed that the glucose at the C5 position of anthocyanin A ring could play a positive role in copigmentation, thus may lead to strong copigmentation effects in these wines.

Different Effects of Quercetin Glycosides and Quercetin on Kidney Mitochondrial Function-Uncoupling, Cytochrome C Reducing and Antioxidant Activity.

Flavonols are found in plants as aglycones and as glycosides. Antioxidant activity of flavonols may occur via several mechanisms within the cell, and mitochondria as a target may play an important role. There is a lack of information about the influence of the sugar moiety on biological activity of flavonoid glycosides. The aims of study were to investigate the effects of quercetin and its glycosides on mitochondrial respiration rates at various metabolic states, and to evaluate their antioxidant potential using chemical and biological approaches. Mitochondrial function was measured using an oxygraphic method, cytochrome c reduction spectrophotometrically, H2O2 generation in mitochondria fluorimetrically, and antioxidant activity of flavonoids using an HPLC-post column system. Our data revealed that quercetin and its glycosides isoquercitrin, rutin, and hyperoside uncouple kidney mitochondrial respiration (increasing the State 2 respiration rate) and significantly reduce cytochrome c. Moreover, quercetin, and its glycosides decrease the production of mitochondrial H2O2 and possess radical scavenging and ferric reducing capacities. The highest activity was characteristic for quercetin, showing that the sugar moiety significantly diminishes its activity. In conclusion, our results show the efficient radical scavenging, ferric and cytochrome c reducing capacities, and uncoupling properties of quercetin and its glycosides, as well as the importance of the sugar residue and its structure in the regulation of kidney mitochondrial function.

DAST-Mediated Fluorination of 1-[4-Thio-β-d-arabinofuranosyl]uracil: Investigation of Thiolane vs Thietane Formation and Stereoselective Synthesis of 4′-ThioFAC

AbstractThe unprecedented DAST-mediated (DAST = diethylaminosulfur trifluoride) deoxygenative fluorination of benzoyl-, TBDPS-, and Bn-protected 1-(β-d-4-thioarabinofuranosyl)uracil at the sugar portion was examined. Three kinds of nucleoside (Ns) products were formed: target thiolane Ns, ring-contracted thietane Ns, and anhydro Ns products. The reaction pathway was determined by the electronic effect of the protecting groups at the sugar and base moieties. The benzoylated uracil starting material gave the 2,2′-anhydronucleoside (anhydro Ns) as a major product, whereas the silylated and benzylated starting materials furnished the corresponding fluorinated products, in which the ring-contracted thietanes predominantly formed. The desired thiolane Ns could be obtained as major product by the addition of a pyridine derivative as an additive. Upon reacting N 3-benzoylated 1-(β-d-4-thioarabinofuranosyl)uracil with DAST in the presence of 2,4,6-collidine, the target 2′-deoxy-2′-β-fluoro-4′-thiouracil nucleoside could be obtained in 72% isolated yield along with the corresponding thietane Ns (7%) and anhydro Ns (3%) (thiolane Ns/thietane Ns/anhydro Ns = 10.3:1.00:0.43), with recovery of the starting material (12%). In this study, the first stereoselective synthesis of the β-anomer of 1-(2-deoxy-2-fluoro-4-thio-β-d-arabino-pentofuranosyl)cytosine (4′-thioFAC) has been developed.