Synthesis and characterization of thiol modified beta cyclodextrin, its biocompatible analysis and application as a modified release carrier of ticagrelor.

Thiol modification of beta cyclodextrin (ß-CD) was carried out using thiourea, which served as a thiol donor. The chemical reaction was mediated using HCl. Polymer prepared via thiolation was further subjected to physicochemical and biocompatible analysis. Acute oral toxicity and compatibility was determined in albino rats. Furthermore, compressed tablets of ticagrelor (TCG) were prepared using modified and unmodified polymers and evaluated via various quality control tests. Thiolation was successfully achieved and confirmed by the FTIR scan, as a significant corresponding peak was observed at 2692 cm-1 wavenumber, demonstrating the attachment of -SH group. In vivo analysis has confirmed the safe use of ß-CD, as none of the vital organs showed any kind of toxic effects. Dissolution studies revealed that Tß-CD was able to release 96.62% of the drug within 1 h of the study, hence providing an immediate release. Conclusively, a thiol moiety was successfully attached to the polymeric backbone and was found safe to be used as a pharmaceutical excipient.

(1-4)-Thiodisaccharides as anticancer agents. Part 5. Evaluation of anticancer activity and investigation of mechanism of action.

(1-4)-Thiodisaccharides, thiosugars with the 1-4-thio bridge, were recently shown to induce oxidative stress, as well as, apoptosis in cancer cells in the low micromolar range; however, the detailed mechanism of their anticancer action still remains unknown. In order to clarify the mechanism of (1-4)- thiodisaccharides action, we performed a series of tests including cytotoxic, clonogenic and apoptosis assays using an in vitro glioma cancer model with one ATCC cell line U87 and two novel glioma cell lines derived from cancer patients - H6PX and H7PX. We also evaluated the ability of (1-4)-thiodisaccharides to interfere with protein folding and synthesis processes, as well as, the thioredoxin system. (1-4)-thiodisaccharides induced glioma cell death, which were found to be accompanied with endoplasmic reticulum stress, inhibition of global protein synthesis, reduced overall cellular thiol level and thioredoxin reductase activity. We also performed a RT-PCR and Elisa analysis of (1-4)-thiodisaccharides-treated glioma cells to identify any changes within the pathway affected by (1-4)-thiodisaccharides. We observed a significant increase of expression in key markers of endoplasmic reticulum stress and pro-apoptotic protein, FASLG. We proposed that (1-4)-thiodisaccharides react with cellular thiols and disturb any cellular thiol-depended processes like thioredoxin system or protein folding.

Salacia chinensis stem extract and its thiosugar sulfonium constituent, neokotalanol, improves HbA1c levels in ob/ob mice.

The antidiabetic effects of a hot water extract of the stems of Salacia chinensis (SCE) were evaluated in vivo in ob/ob mice (genetically obese hyperglycemic mice). Administration of dietary feed containing 0.20 and 0.50% of SCE for 23 days to ob/ob mice significantly suppressed the elevation of both blood glucose and HbA1c levels, without significantly changing body weight and food intake. To characterize the antidiabetic effects of the thiosugar sulfonium constituent neokotalanol (1), which has potent α-glucosidase inhibitory activity, we performed a similar in vivo study. HbA1c levels were significantly suppressed in ob/ob mice after the administration of dietary feed containing 0.0003% of neokotalanol (1) for 20 days. These results indicate that SCE and neokotalanol (1) are potential leads for the development of novel antidiabetic agents.

Selective glycosidase inhibitors: A patent review (2012-present).

In the recent decades, the interest on glycosidases has dramatically increased, mainly because these enzymes play a vital role in many biological processes. Based on the biological potential associated to these enzymes, several glycosidase inhibitors have been developed. In this review, the most important inhibitors targeting these enzymes, including the disaccharides, iminosugars, monocyclic iminosugars, bicyclic iminosugars, thiosugars and carbasugars will be discussed and special attention will be given to the ones that are currently used clinically. This review summarizes and characterizes the current knowledge regarding the classes of glycosidase inhibitors that have therapeutic potential in a wide range of diseases. It highlights the patents, relevant research and patent applications filed in the past years in the field. Since the glycosidase inhibitors are involved in several chronic diseases and possibly pandemic, the pharmaceutical research towards developing new generations of these molecules is very important to public health. Most of the glycosidase inhibitors mimics the structures of monosaccharides or oligosaccharides and are well accepted by the organisms since they benefit from privileged drug-like properties. Disaccharides, iminosugars, carbasugars and thiosugars derivatives are the most popular inhibitors among the glycosidase inhibitors.

Controllable Activation of Pd-G3 Palladacycle Precatalyst in the Presence of Thiosugars: Rapid Access to 1-Aminobiphenyl Thioglycoside Atropoisomers at Room Temperature.

A controllable method for the functionalization of XantPhos Pd-G3 precatalyst with thiosugars and thiols has been established. Under mild and operationally simple reaction conditions through just mixing of precatalyst and thiosugars (α- or ß-mono-, di- and poly-thiosugar derivatives) in water at 25 °C for 20 min, a series of 1-aminobiphenyl thioglycosides that are difficult to synthesize by classical methods has been synthesized in very high yields.

Synthesis and antimicrobial activity of 6-sulfo-6-deoxy-D-glucosamine and its derivatives.

6-Sulfo-6-deoxy-D-glucosamine (GlcN6S), 6-sulfo-6-deoxy-D-glucosaminitol (ADGS) and their N-acetyl and methyl ester derivatives have been synthesized and tested as inhibitors of enzymes catalyzing reactions of the UDP-GlcNAc pathway in bacteria and yeasts. GlcN6S and ADGS at micromolar concentrations inhibited glucosamine-6-phosphate (GlcN6P) synthase of microbial origin. The former was also inhibitory towards fungal GlcN6P N-acetyl transferase, but at millimolar concentrations. Both compounds and their N-acetyl derivatives exhibited antimicrobial in vitro activity, with MICs in the 0.125-2.0 mg mL-1 range. Antibacterial but not antifungal activity of GlcN6S was potentiated by D-glucosamine and a synergistic antibacterial effect was observed for combination of ADGP and a dipeptide Nva-FMDP.

[Thiosugars used as drugs]. / Tiocukry jako leki.

Thiosugars are carbohydrate analogs in which one or few of the oxygen atoms were replaced by sulfur. The sulfur atom which is present in the furan and pyran structures, changes biological properties of carbohydrates, as compared to their oxygen analogs. Among others, thiosugars are effective inhibitors of various cellular and enzymatic pathways and also have great therapeutic potential. They are used as a drugs in diabetes and infectious diseases treatment. Recent evidence suggests that these compounds may have therapeutic properties and be also used in the treatment of some pathological conditions, including cancer diseases. This research are aimed towards the development and improvement of the current methods of synthesis of new thiosugars through stabilization of sulfur bonds and in vitro and in vivo analysis of their potential therapeutic properties. In this work the summary of the latest reports about thiosugars and their application in the medicine is presented for the first time in the Polish language literature.

Binding interaction of SGLT with sugar and thiosugar by the molecular dynamics simulation.

The human sodium-glucose co-transporter 2 (hSGLT2) is a transporter responsible for reabsorption of glucose in the proximal convoluted tubule of the kidney. hSGLT2 inhibitors, including luseogliflozin, have been developed as drugs for type 2 diabetes mellitus. Only luseogliflozin contains a thiosugar ring in its chemical structure, while other hSGLT2 inhibitors contain glucose rings. Consequently, we focused on the binding interactions of hSGLT2 with sugars and thiosugars. We first revealed that the binding affinities of thiosugars are stronger than those of sugars through molecular dynamics simulations of Vibrio parahaemolyticus, sodium-galactose co-transporter, and human hSGLT2. We then demonstrated that Na(+) dissociates from the protein to the cytoplasmic solution more slowly in the thiosugar system than in the sugar system. These differences between sugars and thiosugars are discussed on the basis of the different binding modes due to the atom at the 5-position of the sugar and thiosugar rings. Finally, as a result of Na(+) dissociation, we suggest that the dissociation of thiosugars is slower than that of sugars.

Ruthenium Catalyzed Stereo/Chemo/Regioselective One-Pot Synthesis of C(2)-C(3) Unsaturated and α-D-Mannopyranosyl Sulfones.

An efficient and divergent approach to C(2)-C(3) unsaturated glycosyl and α-D-mannopyranosyl sulfones has been developed via ruthenium-promoted direct glycosylation, oxidation, and dihydroxylation from glycal in one-pot. The presence of stoichiometric amounts of NaIO4 and in situ generation of RuO4 from a RuCl3-NaIO4 reagent system were crucial for chemoselective oxidation of sulfide in the presence of an olefin moiety. The dual-role of ruthenium in sequential glycosylation-oxidation-dihydroxylation is amenable to a wide range of thio acceptors to access α-D-mannopyranosyl sulfones in good yields with high regioselectivity.

Rules and stereoelectronic guidelines for the anionic nucleophilic displacement of furanoside and furanose O-sulfonates.

Rules for predicting anionic SN2 displacement viability in furanose and furanoside sulfonates are presented.

Thio-sugar motif of functional CARB-pharmacophore for antineoplastic activity. Part 2.

Diverse functionalized representatives of (1-4)-S-thiodisaccharides, 6-9 were synthesized and assessed for cytotoxicity and apoptosis against human cancer cell lines (A549, LoVo, MCF-7 and HeLa). The FCP 6 was more active against MCF-7 cells (i.e., an estrogen-dependent breast cancer line), whereas other (1-4)-S-thiodisaccharides showed strongest activity against A549 cells (i.e., a lung adenocarcinoma line). We propose to use a concept of functional 'CARB-pharmacophores' when evaluating a potential for the compounds' general antineoplastic activity. Future studies will determine the reasons for cell-type specificity of these compounds. The thio-sugar motif appears to be a promising lead for future developments.

Synthetic applications of intramolecular thiol-ene "click" reactions.

The intermolecular thiol-ene reaction is emerging as a highly efficient; free-radical mediated "click" process with diverse applications in biofunctionalisation and materials science. The related intramolecular thiol-ene reactions offer significant potential for the preparation of a wide range of sulphur containing heterocycles including synthetic therapeutics such as cyclic peptides and thiosugars. Herein, we review recent advances in intramolecular thiyl-radical mediated reactions and their applications for synthetic and medicinal chemistry.

Applications of 5-exo-trig thiyl radical cyclizations for the synthesis of thiosugars.

The application of thiyl-radical-mediated 5-exo-trig cyclization reactions for the preparation of a series of C-linked 4-thiofuranoside sugars has been investigated. The cyclization reactions were found to proceed in high yield with complete regioselectivity and moderate to excellent diastereoselectivity for a number of benzyl-protected precursors. The diastereoselectivity of the radical cyclization was determined by a number of factors, primarily the stereochemistry at the C-2 position and the nature of the substituents attached to the olefin. The cyclization reactions proceed via transition-state intermediates that favor formation of the 1,2-trans products. For D-sugars, a chairlike transition state is proposed. For L-sugars, both chair- and boatlike transition states could be considered. Inversion of the stereochemistry at C-4 also induced a significant effect on the diastereoselectivity of the radical process. The synthetic route is general for both D- and L-sugars and offers a highly novel and efficient strategy for accessing C-linked 4-thiofuranosides. A fluorescently labeled thiosugar was prepared as a putative glycosidase inhibitor.

Applications of thiyl radical cyclizations for the synthesis of thiosugars.

The use of intramolecular thiyl radical cyclizations for the synthesis of thiosugars has been investigated, and a new free-radical-based methodology for the synthesis of biologically important thiosugars has been developed. The methodology is mild and proceeds via either 6-endo or 5-exo cyclization to furnish the thiosugar ring. This represents the first examples of thiyl radical cyclization being applied to the synthesis of thiosugars.

The first crystal structure of an alkaline metal salt of thioglucose: potassium 1-thio-ß-D-glucoside monohydrate.

In the crystal structure of the title hydrated salt, poly[(µ(2)-aqua)(µ(4)-1-sulfido-ß-D-glucoside)potassium], [K(C(6)H(11)O(5)S)(H(2)O)](n) or K(+)·C(6)H(11)O(5)S(-)·H(2)O, each thioglucoside anion coordinates to four K(+) cations through three of its four hydroxy groups, forming a three-dimensional polymeric structure. The negatively charged thiolate group in each anion does not form an efficient coordination bond with a K(+) cation, but forms intermolecular hydrogen bonds with four hydroxy groups, which appears to sustain the polymeric structure. The Cremer-Pople parameters for the thioglucoside ligand (Q = 0.575, θ = 8.233° and ϕ = 353.773°) indicate a slight distortion of the pyranose ring.

Convenient synthesis of 4-thiolactose, 3,4-dithiolactose and related thiooligosaccharides and disulfides. Inhibitory activity of the glycomimetics against a ß-galactosidase.

The ring-opening reaction of sugar 3,4-epoxides by 2,3,4,6-tetra-O-acetyl-1-thio-ß-D-galactopyranose (7) as a nucleophile led to (1 → 3)- and (1 → 4)-thiodisaccharides. High regio- and diastereoselectivities were achieved in the synthesis of the per-O-acetyl derivative of the ß-D-Galp-S-(1 → 4)-4-thio-α-D-Glcp-O-iPr (10). Analogues of the 4-thiolactoside 10 have been prepared, with the ß-D-Galp non-reducing end S-linked to D-Glcp, D-Gulp and D-Idop. A similar regioselective attack of 7 on C-4 of 2-propyl 3,6-di-O-acetyl-3,4-epithio-α-D-galactopyranoside (6) led to 2-propyl 3,4-dithiolactoside derivative 15. During this reaction the free 3-SH group of 15 underwent oxidative dimerization or oxidative coupling with the SH function of 7 to give the respective disulfides. Glycosylation of the thiol group of 15 using trichloroacetimidate derivatives of ß-D-Galp or ß-D-Galf afforded the corresponding branched dithiotrisaccharides. The free compounds were evaluated as inhibitors of the E. coli ß-galactoside. The bis(2-propyl 3,4-dithiolactosid-3-yl)-disulfide, obtained from 15, displayed the strongest inhibitory activity in these series of glycomimetics and proved to be a non-competitive inhibitor (K(i) = 95 µM).

Multicomponent assembly of proposed DNA precursors in water.

We propose a novel pathway for the prebiotic synthesis of 2'-deoxynucleotides. Consideration of the constitutional chemical relationships between glycolaldehyde and ß-mercapto-acetaldehyde, and the corresponding proteinogenic amino acids, serine and cysteine, led us to explore the consequences of the corresponding sulfur substitution for our previously proposed pathways leading to the canonical ribonucleotides. We demonstrate that just as 2-aminooxazole-an important prebiotic ribonucleotide precursor-is readily formed from glycolaldehyde and cyanamide, so is 2-aminothiazole formed from ß-mercapto-acetaldehyde and cyanamide in water at neutral pH. Indeed, both the oxazole and the thiazole can be formed together in a one-pot reaction, and can be co-purified by crystallization or sublimation. We then show that 2-aminothiazole can take part in a 3-component carbon-carbon bond-forming reaction in water that leads to the diastereoselective synthesis of masked 2'-thiosugars regiospecifically tethered to purine precursors, which would lead to 2'-deoxynucleotides upon desulfurization. The possibility of an abiotic route to the 2'-deoxynucleotides provides a new perspective on the evolutionary origins of DNA. We also show that 2-aminothiazole is able to sequester, through reversible aminal formation, the important nucleotide precursors glycolaldehyde and glyceraldehyde in a stable, crystalline form.

Synthesis of multivalent glycoclusters from 1-thio-ß-D-galactose and their inhibitory activity against the ß-galactosidase from E. coli.

The synthesis of multivalent glycoclusters, designed to be compatible with biological systems, is reported. A variety of 1-thio-ß-D-galactosides linked to a terminal triple bond through oligoethyleneglycol chains of variable lengths has been synthesized. Also, azide-containing oligosaccharide scaffolds were prepared from trehalose, maltose, and maltotriose by direct azidation with NaN(3)/PPh(3)/CBr(4). Click reaction between the thiogalactoside residues and the azide scaffolds under microwave irradiation afforded a family of glycoclusters containing 1 to 4 residues of 1-thio-ß-D-galactose. The yields went from moderate to excellent, depending on the valency of the desired product. Deacetylation with Et(3)N/MeOH/H(2)O led to the final products. Complete characterization of the products was performed by NMR spectroscopy and HR-MS techniques. Their activities as inhibitors of ß-galactosidase from E. coli were determined by using the Lineweaver-Burk method. The use of hydrophilic carbohydrate scaffolds for the synthesis of multivalent galactosides represents an interesting approach to improve their pharmacokinetics and bioavailability. In addition, the presence of the thioglycosidic bond will improve their stability in biological fluids.

Isolation, structure identification and SAR studies on thiosugar sulfonium salts, neosalaprinol and neoponkoranol, as potent α-glucosidase inhibitors.

Two hitherto missing members of sulfonium salts family in Salacia genus plants as a new class of α-glucosidase inhibitors, neoponkoranol (7) and neosalaprinol (8), were isolated from the water extracts, and their structures were unambiguously identified. For further SAR studies on this series of sulfonium salts, several epimers of 7 and 8 were synthesized, and their inhibitory activities against rat small intestinal α-glucosidases were evaluated. Among them, 3'-epimer of 7 was found most potent in this class of molecules, and revealed as potent as currently used antidiabetics, voglibose and acarbose.

Syntheses of p-nitrophenyl 3- and 4-thio-ß-D-glycopyranosides.

Thioglycosides have proved to be useful, enzymatically stable analogs of glycosides for structural and mechanistic studies and their synthesis is considerably simplified through the use of thioglycoligases. As part of an investigation into the use of thioglycosides as potential pharmacological chaperones, and as components of glycoproteins and glycolipids, the syntheses of p-nitrophenyl 3-thio-ß-D-galactopyranoside, phenyl 1,4-dithio-ß-D-glucopyranoside, p-nitrophenyl 4-thio-ß-D-mannopyranoside and p-nitrophenyl 2-acetamido-2-deoxy-4-thio-ß-D-mannopyranoside are described.