4-Thiofuranoid Glycal: Versatile Glycosyl Donor for the Selective Synthesis of -anomer of 4’-thionucleoside and its biological activities

: The first highly diastereoselective synthesis of -anomers of 4’-thionucleosides has been carried out by means of electrophilic glycosidation utilizing 3,5-O-(di-t-butylsilylene) (DTBS)-4-thiofuranoid glycal as a glycosyl donor. The resulting glycosides were transformed into ribo-, 2’-deoxy- and arabinofuranosyl nucleosides through a chemical transformation of the 2’-substituent. The additive Pummerer reaction of the glycal S-oxide gave 1,2-di-O-acetyl-3,5-O-DTBS-4-thioribofuranose. The utility of the DTBS-protected 4-thioribofuranose has been demonstrated by the preparation of 4’-thio analogues of pyrimidine- and purine-4’-thioribonucleosides on the basis of the Vorbrüggen glycosidation. Synthesis of 4’-thio-counterpart of C-nucleoside antibiotic tiazofurin has also been carried out. -Face selective hydroboration of 1-C-aryl- or 1-C-heteroaryl-glycals obtained by cross-coupling of 1-tributylstannylglycal has furnished the respective -anomer of 4’-thio-C-ribonucleosides including 4’-thio analogue of nucleoside antibiotic pseudouridine and 9-deazaadenosine. On the basis of lithiation chemistry, 1-C- and 2-C-carbon-carbon-substituted 3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3- diyl) (TIPDS)- 4-thiofuranoid glycal were synthesized. These glycals enabled us to prepare 1’-C- and 2’--C-carbon-substituted 2’-deoxy-4’-thionucleosides which include thio-counterpart of antitumor nucleoside antibiotic angustmycin C. Furthermore, 1’-C-methyl-4’-thiothymidine emerged as potent inhibitor of angiogenesis. In addition, 1’-C-methyl-4’-thiothymidine exhibited inhibitory activity against thymidine kinase deficient mutant of herpes virus more potent than that of ganciclovir. Among the 4’-substituted 4’-thiothymidines, the 4’-C-cyano- and 4’-C-ethynyl derivatives inhibited replication of HIV variant resistant to 3TC (HIVM184V) as potent as to those of the HIV-1IIIB. In terms of the value of selectivity index (SI), 4’-C-cyano-4’-thiothymidine showed 3-fold selective index (SI) than that of the corresponding thymidine derivative. Furthermore, 4’-C-ethynyl-2’-deoxy-4’-thioguanosine has a 20-fold better value (>18,200) than that of 2’-deoxyguanosine counterpart (933). Furthermore,4’-azido-4’-thiothymidine was emerged as selective and potent anti-EBV agent. In terms of antineoplastic activity, 4’-azido- and 4’-C-fluoromethyl-2’-deoxy-4’-thiocytidine inhibited proliferation of human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines although the parent compound 2’-deoxy-4’-thiocytidine did not show any cytotoxicity up to 100 M. These facts concerning the biological activities suggested that replacement of the furanose oxygen with sulfur atom is a promising approach for development of less toxic antiviral and antineoplastic nucleoside antimetabolites. 4’-Thionucleoside has also superior biological properties as monomer for oligonucleotides (ONs) therapeutics. Therefore, this review provides a wide range of potential monomer for antisense ON and siRNA.

Identification and Characterization of a Thermostable GH36 α-Galactosidase from Anoxybacillus vitaminiphilus WMF1 and Its Application in Synthesizing Isofloridoside by Reverse Hydrolysis

An α-galactosidase-producing strain named Anoxybacillus vitaminiphilus WMF1, which catalyzed the reverse hydrolysis of d-galactose and glycerol to produce isofloridoside, was isolated from soil. The α-galactosidase (galV) gene was cloned and expressed in Escherichia coli. The galV was classified into the GH36 family with a molecular mass of 80 kDa. The optimum pH and temperature of galV was pH 7.5 and 60 °C, respectively, and it was highly stable at alkaline pH (6.0–9.0) and temperature below 65 °C. The specificity for p-nitrophenyl α-d-galactopyranoside was 70 U/mg, much higher than that for raffinose and stachyose. Among the metals and reagents tested, galV showed tolerance in the presence of various organic solvents. The kinetic parameters of the enzyme towards p-nitrophenyl α-d-galactopyranoside were obtained as Km (0.12 mM), Vmax (1.10 × 10−3 mM s−1), and Kcat/Km (763.92 mM−1 s−1). During the reaction of reverse hydrolysis, the enzyme exhibited high specificity towards the glycosyl donor galactose and acceptors glycerol, ethanol and ethylene glycol. Finally, the isofloridoside was synthesized using galactose as the donor and glycerol as the acceptor with a 26.6% conversion rate of galactose. This study indicated that galV might provide a potential enzyme source in producing isofloridoside because of its high thermal stability and activity.

The Synthesis of Blood Group Antigenic A Trisaccharide and Its Biotinylated Derivative

Blood group antigenic A trisaccharide represents the terminal residue of all A blood group antigens and plays a key role in blood cell recognition and blood group compatibility. Herein, we describe the synthesis of the spacered A trisaccharide by means of an assembly scheme that employs in its most complex step the recently proposed glycosyl donor of the 2-azido-2-deoxy-selenogalactoside type, bearing stereocontrolling 3-O-benzoyl and 4,6-O-(di-tert-butylsilylene)-protecting groups. Its application provided efficient and stereoselective formation of the required α-glycosylation product, which was then deprotected and subjected to spacer biotinylation to give both target products, which are in demand for biochemical studies.

Physiological and transcriptome analysis elucidates the metabolic mechanism of versatile Porphyridium purpureum under nitrogen deprivation for exopolysaccharides accumulation

Porphyridium purpureum is a mesophilic, unicellular red alga rich in phycoerythrin, sulfate polysaccharides, and polyunsaturated fatty acids. Nitrogen deficiency inhibited the growth of P. purpureum and resulted in yellowing of the cells and thickening of the extracellular viscousness sheath. Under nitrogen stress, the contents of total lipids and exopolysaccharides in P. purpureum were increased by 65.2% and 188.0%, respectively. We demonstrate that the immediate response of P. purpureum to nitrogen deficiency is mediated by carbon flow to polysaccharide synthesis, while the synthesis of lipids is enhanced as a permanent energy storage substance at the later stage. Based on transcriptome annotation information, we elucidate the synthesis pathway of polysaccharides from P. purpureum from the perspective of glycosyl-donor interconversion, and demonstrate that the n-6 pathway is the main synthesis pathway of polyunsaturated fatty acids. This study not only provides a production strategy for polysaccharides and fatty acids by single-celled marine red algae P. purpureum, but also provides targets for further genetic modification.

Chemo-enzymatic synthesis of Lacto-N-biose I catalyzed by β-1,3 galactosidase from Bacillus circulans using 4,6-dimethoxy-1,3,5-triazin-2-yl β-galactopyranoside as a glycosyl donor

Chemo-enzymatic synthesis of lacto-N-biose I (LNB) catalyzed by β-1,3 galactosidase from Bacillus circulans (BgaC) has been developed using 4,6-dimethoxy-1,3,5-triazin-2-yl β-galactopyranoside [DMT-β-Gal] and GlcNAc as the donor and acceptor substrates, respectively. BgaC transferred the Gal moiety to the acceptor, giving rise to LNB. The maximum yield of LNB was obtained at the acceptor: donor substrate ratio of 1:30.

A One-Pot Approach to Novel Pyridazine C-Nucleosides

The synthesis of glycosides and modified nucleosides represents a wide research field in organic chemistry. The classical methodology is based on coupling reactions between a glycosyl donor and an acceptor. An alternative strategy for new C-nucleosides is used in this approach, which consists of modifying a pre-existent furyl aglycone. This approach is applied to obtain novel pyridazine C-nucleosides starting with 2- and 3-(ribofuranosyl)furans. It is based on singlet oxygen [4+2] cycloaddition followed by reduction and hydrazine cyclization under neutral conditions. The mild three-step one-pot procedure leads stereoselectively to novel pyridazine C-nucleosides of pharmacological interest. The use of acetyls as protecting groups provides an elegant direct route to a deprotected new pyridazine C-nucleoside.

Progress and Achievements in Glycosylation of Flavonoids

In recent years, the chemistry of flavonoid glycosylation has undergone significant developments. This mini-review is devoted to summarizing existing strategies and methods for glycosylation of natural and synthetic flavonoids. Herein we overviewed the reaction conditions of flavonoid glycosylation depending on the position of hydroxyl groups in a parent molecule, the degree of it conjugation with the π-system, the presence of steric factors, the formation of intramolecular hydrogen bonds, etc. Especial attention was given to the choice of the glycosyl donor moiety, which has a significant effect on the yield of the final glycosidated products. Finally, a general strategy for regioselective glycosylation of flavonoids containing several hydroxyl groups is outlined.

A Practical, Component-Based Synthetic Route to Methylthiolincosamine Permitting Facile Northern-Half Diversification of Lincosamide Antibiotics

The development of a flexible, component-based synthetic route to the aminosugar fragment of the lincosamide antibiotics is described. This synthetic route hinges on the application and extension of nitroaldol chemistry to forge strategic bonds within complex aminosugar targets, and employs a glycal epoxide as a versatile glycosyl donor for the installation of various anomeric groups. Through building-block exchange and late-stage functionalization, this route affords access to a host of rationally designed lincosamides otherwise inaccessible by semisynthesis, and underpins a platform for the discovery of new lincosamide antibiotics.