Clinical Effect of Thioglycosides Extracted from White Mustard on Dental Plaque and Gingivitis: Randomized, Single-Blinded Clinical Trial.

The antibacterial and anti-inflammatory effect of thioglycosides has already been established. This study investigates the effects of thioglycosides extracted from white mustard, specifically the "Bamberka" variety, in the context of oral hygiene. The aim of the study is to clarify an evidence-based link between the documented antibacterial and anti-inflammatory effects attributed to thioglycosides and their practical application in oral care. A randomized, single-blinded (patient-blinded) clinical study was performed on 66 patients using mustard-based toothpaste for oral hygiene. The patients were examined at baseline and after 6 and 12 months. The values of the Approximal Plaque Index (API), the Plaque Index (PI), and Bleeding on probing (BOP) were taken into consideration. The results show a significant reduction in plaque accumulation, especially after 6 months of using mustard-based toothpaste in all examined parameters. This suggests that thioglycosides from mustard contribute to a considerable decrease in dental plaque accumulation, confirming their potential in natural oral care solutions, which is indicated in the main conclusions or interpretations.

Novel dihydropyridine thioglycosides and their corresponding dehydrogenated forms as potent anti-hepatocellular carcinoma agents.

A novel method for preparation of a new class of dihydropyridine thioglycosides and their corresponding dehydrogenated forms, via reaction of piperidinium salts of dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and galactopyranosyl bromides has been studied. The evaluation of antiproliferative activity against HepG-2 cell lines (liver carcinoma cell lines) of the dihydropyridine thioglycosides and pyridine thioglycosides revealed that many of the thioglycosides have interesting antitumor activities specifically 5c, 5g, 5l, 5o, 5p, 7a, 7i, 7p, 8b, 8f, 8s, and 8v.

Design, synthesis, molecular docking and anti-hepatocellular carcinoma evaluation of novel acyclic pyridine thioglycosides.

A novel series of acyclic pyridine thioglycosides has been synthesized. Evaluation of the anti proliferative activity of these compounds against HEPG-2 cell lines (liver carcinoma cell lines) shows that most of the compounds have high anti-tumor activities especially 6b, 6c, 7b and 7c. Furthermore, in the modeling study, these compounds showed that they have high binding affinity with thymidylate synthase dihydrofolate reductase (TS-DHFR).

Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition.

Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3-glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3'-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3, together with galectin-3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin-3. The most potent galectin-3 antagonist was demonstrated to act in an assay monitoring galectin-3 accumulation upon amitriptyline-induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin-carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin-induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.

Antihyperglycaemic activity of 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal in diabetic mice.

We have recently generated lipophilic D-xylose derivatives that increase the rate of glucose uptake in cultured skeletal muscle cells in an AMP-activated protein kinase (AMPK)-dependent manner. The derivative 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal (EH-36) stimulated the rate of glucose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of cultured myotubes. The present study aimed at investigating potential antihyperglycaemic effects of EH-36 in animal models of diabetes. Two animal models were treated subcutaneously with EH-36: streptozotocin-induced diabetes in C57BL/6 mice (a model of insulin-deficient type 1 diabetes), and spontaneously diabetic KKAy mice (Kuo Kondo rats carrying the A(y) yellow obese gene; insulin-resistant type 2 diabetes). The in vivo biodistribution of glucose in control and treated mice was followed with the glucose analogue 2-deoxy-2-[(18) F]-D-glucose; the rate of glucose uptake in excised soleus muscles was measured with [(3) H]-2-deoxy-D-glucose. Pharmacokinetic parameters were determined by non-compartmental analysis of the in vivo data. The effective blood EH-36 concentration in treated animals was 2 µM. It reduced significantly the blood glucose levels in both types of diabetic mice and also corrected the typical compensatory hyperinsulinaemia of KKAy mice. EH-36 markedly increased glucose transport in vivo into skeletal muscle and heart, but not to adipose tissue. This stimulatory effect was mediated by Thr(172) -phosphorylation in AMPK. Biochemical tests in treated animals and acute toxicological examinations showed that EH-36 was well tolerated and not toxic to the mice. These findings indicate that EH-36 is a promising prototype molecule for the development of novel antidiabetic drugs.

Galectin-3 targeted therapy with a small molecule inhibitor activates apoptosis and enhances both chemosensitivity and radiosensitivity in papillary thyroid cancer.

Although most patients with papillary thyroid cancer (PTC) have favorable outcomes, some have advanced PTC that is refractory to external beam radiation and systemic chemotherapy. Galectin-3 (Gal-3) is a beta-galactoside-binding protein with antiapoptotic activity that is consistently overexpressed in PTC. The purpose of this study is to determine if Gal-3 inhibition promotes apoptosis, chemosensitivity, and radiosensitivity in PTC. PTC cell lines (8505-C and TPC-1) and human ex vivo PTC were treated with a highly specific small molecule inhibitor of Gal-3 (Td131_1). Apoptotic activity was determined by flow cytometric analysis as well as caspase-3 and PARP cleavage. The minimum inhibitory concentrations of Td131_1 and doxorubicin were determined, and their combined effects were measured to test for synergistic activity. The effects of Td131_1 on radiosensitivity were determined by a clonogenic assay. Td131_1 promoted apoptosis, improved radiosensitivity, and synergistically enhanced chemosensitivity to doxorubicin in PTC cell lines. In PTC ex vivo, Td131_1 treatment alone induced the cleavage of caspase-3 and PARP. Td131_1 and doxorubicin together activated apoptosis in PTC ex vivo to a greater degree than their combined individual effects. Td131_1 activated apoptosis and had synergistic activity with doxorubicin in PTC. We conclude that Gal-3 targeted therapy is a promising therapeutic strategy for advanced PTC that is refractory to surgery and radioactive iodine therapy.

Thioglycosides as inhibitors of hSGLT1 and hSGLT2: potential therapeutic agents for the control of hyperglycemia in diabetes.

The treatment of diabetes has been mainly focused on maintaining normal blood glucose concentrations. Insulin and hypoglycemic agents have been used as standard therapeutic strategies. However, these are characterized by limited efficacy and adverse side effects, making the development of new therapeutic alternatives mandatory. Inhibition of glucose reabsorption in the kidney, mediated by SGLT1 or SGLT2, represents a promising therapeutic approach. Therefore, the aim of the present study was to evaluate the effect of thioglycosides on human SGLT1 and SGLT2. For this purpose, stably transfected Chinese hamster ovary (CHO) cells expressing human SGLT1 and SGLT2 were used. The inhibitory effect of thioglycosides was assessed in transport studies and membrane potential measurements, using alpha-methyl-glucoside uptake and fluorescence resonance energy transfer, respectively. We found that some thioglycosides inhibited hSGLT more strongly than phlorizin. Specifically, thioglycoside I (phenyl-1'-thio-beta-D-glucopyranoside) inhibited hSGLT2 stronger than hSGLT1 and to a larger extent than phlorizin. Thioglycoside VII (2-hydroxymethyl-phenyl-1'-thio-beta-D-galacto-pyranoside) had a pronounced inhibitory effect on hSGLT1 but not on hSGLT2. Kinetic studies confirmed the inhibitory effect of these thioglycosides on hSGLT1 or hSGLT2, demonstrating competitive inhibition as the mechanism of action. Therefore, these thioglycosides represent promising therapeutic agents for the control of hyperglycemia in patients with diabetes.

Thiosugars: new perspectives regarding availability and potential biochemical and medicinal applications.

Thiosugars, containing a sulfur atom as heteroatom or a disaccharide linked via a sulfur bridge, possess unique physicochemical properties such as water solubility, which differs from conventional functionalized monosaccharides. The differences in biological activities between thiosugars and their oxygen analogs depend on geometric, conformational, and flexibility differences. They depend also on their electronic differences, the sulfide function being less electronegative and more polarizable than the ethereal moiety. Many functionalized thiosugars occur naturally and are potential targets for the development of carbohydrate-based therapeutics. Among the few new examples of the potential new targets are salacinol and kotalanol, tagetitoxin, thiolactomycin and analogues, mycothiol and analogues, and S-nitrosothiols. These new developments and representative examples of functionalized thiosugar prototypes as potential new targets are presented in this mini review.

New 1-C-(5-thio-D-xylopyranosyl) derivatives as potential orally active venous antithrombotics.

In the search for new orally active antithrombotic drugs that are metabolically stable, we explored the synthesis of 1-C-(5-thio-D-xylosyl) derivatives, examining radical and nucleophilic methods. Thus synthesized were aryl, benzyl, alkylcarboxymethylenyl, arylsulfonylmethylenyl and alkylaminocarboxymethylenyl C-linked analogues of 5-thio-D-xylopyranosides.

Synthesis of 4-cyano- and 4-nitrophenyl 2,5-anhydro- 1,6-dithio-alpha-D-gluco- and -alpha-L-guloseptanosides carrying different substituents at C-3 and C-4.

Treatment of 1,6:2,5-dianhydro-3,4-di-O-methanesulfonyl-1-thio-D-glucitol in methanol with sodium hydroxide afforded 1,6:2,5:3,4-trianhydro-1-thio-allitol, 1,4:2,5-dianhydro-6-methoxy-1-thio-D-galactitol, 1,6:2,5-dianhydro-4-O-methyl-1 -thio-D-glucitol, 1 ,6:2,5-dianhydro-3-O-methanesulfonyl-1 -thio-D-glucitol and 1 ,6:2,5-dianhydro-4-deoxy-1-thio-D-erythro-hex-3-ulose (14) in 5, 4, 28, 5.5 and 41% yield, respectively. Formation of these derivatives can be explained via a common sulfonium intermediate. Reduction of 14 with sodium borohydride and subsequent acetylation afforded 3-O-acetyl-1,6:2,5-dianhydro-4-deoxy-1-thio-D-xylo-hexitol, the absolute configuration of which was proved by X-ray crystallography. The 1,6:2,5-dianhydro-1-thio-D-hexitol derivatives in which the free OH groups were protected by acetylation, methylation or mesylation were converted by a Pummerer reaction of their sulfoxides into the corresponding 1-O-acetyl hexoseptanose derivatives which were used as donors for the glycosidation of 4-cyano- and 4-nitrobenzenethiol, respectively. The Pummerer reaction of 1,6:2,5-dianhydro-4-deoxy-3-O-methyl-1-thio-D-xylo-hexitol S-oxide gave, besides 1-O-acetyl-2,5-anhydro-3-deoxy-4-O-methyl-6-thio-alpha-L- (23) and 1-O-acetyl-2,5-anhydro-4-deoxy-3-O-methyl-6-thio-alpha-D-xylo-hexoseptanose (25), 1-O-acetyl-4-deoxy-2,6-thioanhydro-D-lyxo-hexopyranose, formed in a rearrangement reaction. The same rearrangement took place, when a mixture of 23 and 25 was used as donor in the glycosidation reaction with 4-cyanobenzenethiol, applying trimethylsilyl triflate as promoter. The oral antithrombotic activity of the obtained alpha-thioglycosides was determined in rats, using Pescador's model.

Thio sugars: biological relevance as potential new therapeutics.

The biological relevance of sulfur containing carbohydrates is gaining substantial attention. Thus the new developments, especially in the synthetic and medicinal chemistry of thio-sugars are critically important for carbohydrate drug design. New studies of biological processes including biosynthetic reactions and enzyme control mechanisms, discovered during the last few years clearly contributed to an understanding of their biological roles. These roles of carbohydrates and thio-sugars in particular through biological processes and diseases are becoming better understood now. These new trends will provide tremendous opportunities for the development of carbohydrates as new potential drugs. The main objective of this article is to address these new promising advances