Odorless benzenethiols in synthesis of thioglycosides and its application for glycosylation reactions

p-Octyloxybenzenethiol (2) was synthesized as a new odorless benzenethiol. Moreover, preparation of thioglycosides using 2 and their application for glycosylation reactions were attempted. As a result, it was found that the thioglycosides were as excellent glycosyl donors as 4-dodecylphenyl 1-thio-glycosides, which were previously reported by our group, and more useful than the previous donors in terms of fine chemistry in glycosylation reaction activated with silver triflate and N-iodosuccinimide (NIS). In addition, this method was applicable to the sialylation with NIS and triflic acid. All procedures from the preparation of thioglycosides to the glycosylation reaction could be attained completely under conditions where no malodor was generated.     

Synthetic studies on glycosphingolipids from Protostomia phyla: total syntheses of glycosphingolipids from the parasite, Echinococcus multilocularis

Efficient and systematic syntheses of four neutral glycosphingolipids that have been isolated from the metacestodes of Echinococcus multilocularis have been achieved. A key step is the direct glycosylation of galactosyl donors using thioglycosides with benzoyl ceramide in the presence of N-iodosuccinimide (NIS)/TfOH, which gave the desired oligosaccharide derivatives. The fully protected glycosides 13, 20, 22 and 25 were deprotected to give four target glycosphingolipids (1-4).     

NIS/TFA: a general method for hydrolyzing thioglycosides

A variety of thioglycosides are chemoselectively hydrolyzed to the corresponding 1-hydroxy glycosides using equimolar amounts of NIS/TFA as promoter systems.     

Evaluation of thioglycosides of Kdo as glycosyl donors

The use of Kdo thioglycosides as glycosyl donors using DMTST, IBr/AgOTf and NIS/AgOTf as promoters has been evaluated. Activation at low temperature allowed to escape the formation of 2,3-glycal byproducts to give glycosides in high yield and with good beta-anomeric selectivity. The use of diethyl ether as solvent and (especially) isopropylidene acetals as protecting groups improved the alpha-anomeric selectivity. NIS/AgOTf as promoter surprisingly yielded the 3-iodo-product via the glycal intermediate.     

Synthesis of aryl-2-deoxy-D-lyxo/arabino-hexopyranosides from 2-deoxy-1-thioglycosides

The synthesis of either anomers of aryl 2-deoxy-D-glycopyranosides from 2-deoxy-1-thioglycosides is reported. The alpha-anomers form as the major product when thioglycosides react with differently substituted phenols and naphthols, in the presence of N-iodosuccinimide/triflic acid. On the other hand, reaction of the thioglycosides with bromine initially, followed by reaction with aryloxy anions lead to aryl 2-deoxy-beta-D-glycosides with high specificities.     

NIS/H2SO4-Silica: a mild and efficient reagent system for the hydrolysis of thioglycosides

Chemoselective hydrolysis of a variety of thioglycosides in the presence of a wide range of protecting groups has been achieved by using N-iodosuccinimide and H(2)SO(4) immobilized on silica in good to excellent yields.     

Synthesis of biantennary beta-D-(1-->6) glucosamine oligosaccharides

Biantennary beta-D-(1-->6) glucosamine hexa-, octa-, and dodecaoligosaccharide derivatives were synthesized convergently using isopropyl thioglycosides as donors in NIS/TMSOTf-catalyzed glycosylation.     

Low Iodine in the Follicular Lumen Caused by Cytoplasm Mis-localization of Sodium Iodide Symporter may Induce Nodular Goiter

Iodine is a key ingredient in the synthesis of thyroid hormones and also a major factor in the regulation of thyroid function. A local reduction of iodine content in follicular lumen leads to overexpression of local thyroid-stimulating hormone receptor (TSHr), which in turn excessively stimulates the regional thyroid tissue, and result in the formation of nodular goiter. In this study, we investigated the relationship between iodine content and sodium iodide symporter (NIS) expression by using the clinical specimens from patients with nodular goiter and explored the pathogenesis triggered by iodine deficiency in nodular goiter. In total, 28 patients were clinically histopathologically confirmed to have nodular goiter and the corresponding adjacent normal thyroid specimens were harvested simultaneously. Western blot and immunohistochemistry were performed to assay NIS expression and localization in thyrocytes of both nodular goiter and adjacent normal thyroid tissues. NIS expression mediated by iodine in follicular lumen was confirmed by follicular model in vitro. Meanwhile, radioscan with iodine-131were conducted on both nodular goiter and adjacent normal thyroid. Our data showed that NIS expression in nodular goiter was significantly higher than that in adjacent normal tissues, which was associated with low iodine in the follicular lumen. Abnormal localization of NIS and lower amount of radioactive iodine-131 were also found in nodular goiter. Our data implied that low iodine in the follicular lumen caused by cytoplasm mis-localization of NIS may induce nodular goiter.     

Synthesis of octyl arabinofuranosides as substrates for mycobacterial arabinosyltransferases

A panel of octyl oligosaccharides comprised of arabinofuranose rings have been synthesized via efficient and readily scaleable routes. The key glycosylation reactions involved the coupling of octyl glycoside acceptors with the appropriate thioglycosides using N-iodosuccinimide and silver triflate activation. These syntheses were undertaken to provide substrates suitable for use in assays of mycobacterial arabinosyltransferases.     

Reactivity switching and selective activation of C-1 or C-3 in 2,3-unsaturated thioglycosides

Reactivity switching and selective activation of C-1 or C-3 in 2,3-unsaturated thioglycosides, namely, 2,3-dideoxy-1-thio-d-hex-2-enopyranosides are reported. The reactivity switching allowed activation of either C-1 or C-3, with the use of either N-iodosuccinimide (NIS)/triflic acid (TfOH) or TfOH alone. C-1 glycosylation with alcohol acceptors occurred in the presence of NIS/TfOH, without the acceptors reacting at C-3. On the other hand, reaction of 2,3-unsaturated thioglycosides with alcohols mediated by triflic acid led to transposition of C-1 ethylthio-moiety to C-3 intramolecularly, to form 3-ethylthio-glycals. Resulting glycals underwent glycosylation with alcohols to afford 3-ethylthio-2-deoxy glycosides. However, when thiol was used as an acceptor, only a stereoselective addition at C-3 resulted, so as to form C-1, C-3 dithio-substituted 2-deoxypyranosides.     

A practical synthesis of a (1-->6)-linked beta-D-glucosamine nonasaccharide

A (1-->6)-beta-D-glucosamine nonasaccharide was convergently synthesized using isopropyl thioglycosides as donors. Anomeric acetylated glucosamine derivatives were proved to be good acceptors in the NIS/TMSOTf catalyzed glycosylation. The target nonasaccharide showed a mild antitumor activity against H22 on the preliminary mice tests.     

Synthesis of 2-iodo-2-deoxy septanosides from a D-xylose-based oxepine: intramolecular cyclization in the absence of a glycosyl acceptor

Oxidative glycosylations of the D-xylose-based oxepine 1,6-anhydro-3,4,5-tri-O-benzyl-2-deoxy-D-xylosept-1-enitol (1) using N-iodosuccinimide (NIS) are reported. The reaction produced 2-deoxy-2-iodo-alpha-D-idoseptanosides and 2-deoxy-2-iodo-beta-D-guloseptanosides 2-9 in good yields. When limited equivalents of a glycosyl acceptor were used, or in the absence of a glycosyl acceptor, an intramolecular cyclization predominated to form 1,6-anhydro-3,4-di-O-benzyl-2-deoxy-2-iodo-alpha-D-idopyranose (10).     

Na+/I− Symporter and Type 3 Iodothyronine Deiodinase Gene Expression in Amniotic Membrane and Placenta and Its Relationship to Maternal Thyroid Hormones

Placental type 3 iodothyronine deiodinase (D3) potentially protects the fetus from the elevated maternal thyroid hormones. Na⁺/I^? symporter (NIS) is a plasma membrane glycoprotein, which mediates active iodide uptake. Our objectives were to establish the distribution of NIS and D3 gene expressions in the placenta and the amniotic membrane and to investigate the relationship between placental D3 and NIS gene expressions and maternal iodine, selenium, and thyroid hormone status. Thyroid hormones, urinary iodine concentration (UIC), and selenium levels were measured in 49 healthy term pregnant women. NIS and D3 gene expressions were studied with the total mRNA RT-PCR method in tissues from maternal placenta (n?=?49), fetal placenta (n?=?9), and amniotic membrane (n?=?9). NIS and D3 gene expressions were shown in the fetal and maternal sides of the placenta and amniotic membrane. Mean blood selenium level was 66?±?26.5 μg/l, and median UIC was 143 μg/l. We could not demonstrate any statistically significant relationship of spot UIC and blood selenium with NIS and D3 expression (p?>?0.05). Positive correlations were found between NIS and thyroxine-binding globulin (TBG) (r?=?0.3, p?=?0.042) and between D3 and preoperative glucose levels (r?=?0.4, p?=?0.006). D3 and NIS genes are expressed in term placenta and amniotic membrane; thus, in addition to placenta, amniotic membrane contributes to regulation of maternofetal iodine and thyroid hormone transmission. Further studies are needed to clarify the relationship between maternal glucose levels and placental D3 expression and between TBG and placental NIS expression.     

Synthesis of neutral glycosphingolipids from Zygomycetes

Novel neutral glycosphingolipids (NGSLs) containing Gal-alpha1-->6Gal, previously found in the Zygomycetes species Mucor hiemalis, were synthesized. The structures of these compounds are different from those of other fungal GSLs, and they are expected to be involved in host-parasite interactions. A key step in their synthesis is direct 1,2-cis alpha-selective galactosylation of 4,6-diol tri- and tetrasaccharide acceptors with a galactosyl donor in the presence of N-iodosuccinimide (NIS)/trifluoromethanesulfonic acid (TfOH). The fully protected glycosides were deprotected to give the two target glycosphingolipids.     

Synthesis of two trisaccharides related to the triterpenoid saponins isolated from Solanum lycocarpum

Chemical synthesis of two trisaccharides related to the triterpenoid saponins isolated from Solanum lycocarpum from commercially available d-Glc, d-Gal and l-Rha have been achieved by following concise and high-yielding route. The target trisaccharide 1 has been made by following a bis-glycosylation approach that has minimized the protecting group manipulations up to great extent. The trisaccharides have been synthesized in the form of their p-methoxyphenyl (OMP) glycosides to leave the scope for further glycoconjugates formation by the selective removal of the OMP glycoside and trichloroacetimidate chemistry. La(OTf)₃ has been used successfully as the promoter for the NIS mediated activation of thioglycosides.     

Synthesis of new, potent avermectin-like insecticidal agents

4'-Modified avermectin derivatives were designed and synthesized. Some of the new synthetic compounds showed excellent in vivo bioactivity against cabbage larvae when compared to commercially available avermectin B1a. In this synthesis, uncommon thioglycosyl sugar donors, prepared from the hydrolysis of natural antibiotics, proved compatible with sugar-macrolide synthesis in the presence of N-iodosuccinimide (NIS) or I2 in N-methylpyrrolidone at room temperature.     

Scope and limitations of imidazolium-based ionic liquids as room temperature glycosylation promoters

The scope and limitations of imidazolium-based ionic liquids as room temperature glycosylation promoters have been studied. Herein, we report the effects of modifying the structure of the imidazolium cation and how important the choice of counter ion becomes on model glycosylation reactions of thioglycosides at room temperature in the presence of N-iodosuccinimide (NIS).     

Propensity Score-Matched Analysis to Identify Pathways Associated with Loss of Sodium Iodide Symporter in Papillary Thyroid Cancer

Sodium iodide symporter (NIS) expression in thyroid follicular cells plays an important role in normal physiology and radioactive iodine therapy for thyroid cancer. Loss of NIS expression is often seen in thyroid cancers and may lead to radioiodine refractoriness. To explore novel mechanisms of NIS repression beyond oncogenic drivers, clinical and RNA-seq data from the thyroid cancer dataset of The Cancer Genome Atlas were analyzed. Propensity score matching was used to control for various genetic background factors. We found that tumoral NIS expression was negatively correlated with tumor size. Additionally, low NIS expression was the only factor associated with recurrence-free survival in a Cox multivariate regression analysis. After matching for clinicopathologic profiles and driver mutations, the principal component analysis revealed distinct gene expressions between the high and low NIS groups. Gene set enrichment analysis suggested the downregulation of hedgehog signaling, immune networks, and cell adhesions. Positively enriched pathways included DNA replication, nucleotide excision repair, MYC, and Wnt/β-catenin pathways. In summary, we identified several potential targets which could be exploited to rescue the loss of NIS expression and develop redifferentiation strategies to facilitate radioactive iodine therapy for thyroid cancer.