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.

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation.

Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC50= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 µM, respectively, for compound 8), (IC50 = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 µM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC50 = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 µM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field.

New bis-thioglycosyl-1,1'-disulfides from Nasturtium officinale R. Br. and their anti-neuroinflammatory effect.

As a part of our continuing search for bioactive constituents from Brassicaceae family, three new bis-thioglycosides (1-3) were isolated from the 80% MeOH extract of Nasturtium officinale, together with 13 known compounds (4-16). The chemical structures of three new bis-thioglycosides (1-3) were elucidated using NMR techniques (1H and 13C NMR, 1H-1H COSY, HSQC, and HMBC), HRESIMS, and a chemical method. All the compounds were evaluated for their inhibitory effects on nitric oxide (NO) levels in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells. Among the isolates, compound 5 exhibited a strong inhibitory effect on NO production, and compounds 4 and 15 showed moderate inhibitory activities, suggesting the neuroprotective and anti-neuroinflammatory effects of bis-thioglycosides from N. officinale.

Water soluble thioglycosylated BODIPYs for mitochondria targeted cytotoxicity.

The facile synthesis of water-soluble mitochondria targeting thioglycosylated BODIPYs is reported. Thioglycosylated BODIPYs were synthesized in 25-26% yields via thioglycosylated dipyrromethanes in four steps. The dipyrromethanes and thioglycosylated BODIPYs were characterized by various techniques including HRMS, NMR spectroscopy and X-ray crystallography. In-vitro cellular investigations in skin keratinocyte (HaCaT) and cervical (HeLa) cancer cells revealed significant cytotoxicities with IC50 values between 23.83 to 48.61 µM. The flow cytometry experiments revealed significant cellular uptake of thioglycosylated BODIPYs into HaCaT cells and thioglucosyl substituted BODIPY (9) showed higher cellular uptake and ROS generation than the rest of the molecules. The highlight of this study is the mitochondrial targeting by the neutral BODIPYs, as judged by the colocalization experiments using confocal microscopy.

Synthesis and Cytotoxic Activity of New 1,3,4-Thiadiazole Thioglycosides and 1,2,3-Triazolyl-1,3,4-Thiadiazole N-glycosides.

New 1,3,4-thiadiazole thioglycosides linked to substituted arylidine systems were synthesized via glycosylation of the prepared 1,3,4-thiadiazole thiol compounds. Click strategy was also used for the synthesis of new 1,3,4-thiadiazole and 1,2,3-triazole hybrid glycosides by reaction of the acetylenic derivatives with different glycosyl azids followed by deacetylation process. The cytotoxic activities of the prepared compounds were studied against HCT-116 (human colorectal carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines using the MTT assay. The results showed that the key thiadiazolethione compounds 2 and 3, the triazole glycosides linked to p-methoxyarylidine derivatives 14 and 15 in addition to the free hydroxyl glycoside 20 were found potent in activity comparable to the reference drug doxorubicin against MCF-7 human cancer cells. The acetylenic derivative 2 and glycoside 20 were also found highly active against HCT-116 cell lines.

Selective inhibition of ß-N-acetylhexosaminidases by thioglycosyl-naphthalimide hybrid molecules.

To develop selective inhibitors for ß-N-acetylhexosaminidases which are involved in a myriad of physiological processes, a series of novel thioglycosyl-naphthalimide hybrid inhibitors were designed, synthesized and evaluated for inhibition activity against glycosyl hydrolase family 20 and 84 (GH20 and GH84) ß-N-acetylhexosaminidases. These compounds which incorporate groups with varied sizes and lengths at the linker region between thioglycosyl moiety and naphthalimide moiety are designed to improve the selectivity and stacking interactions. The GH84 human O-GlcNAcase (hOGA) was sensitive to the subtle changes in the linker region and the optimal choice is a small size linker with six atoms length. And the GH20 insect ß-N-acetylhexosaminidase OfHex1 could tolerate compounds with a hydrophobic bulky linker. Especially, the compound 5c (hOGA, Ki = 3.46 µM; OfHex1, Ki > 200 µM) and the compound 6f (hOGA, Ki > 200 µM; OfHex1, Ki = 21.81 µM) displayed high selectivity. The molecular docking results indicated that the inhibition mechanism was different between the two families due to their different structural characteristics beyond the active sites. These results provide some promising clues to improve selectivity of potent molecules against ß-N-acetylhexosaminidases.

Rare Thioglycosides from the Roots of Wasabia japonica.

Six new thioglycosides (1-6) were characterized from the roots of Wasabia japonica along with a known analogue (7). Of these compounds, 1-3 possess a disulfide bridge connecting the carbohydrate motif and the aglycone, which is extremely rare in Nature. In particular, compound 1 forms an unusual 1,4,5-oxadithiocane ring system. The structures of the isolated compounds were determined through conventional NMR and HRMS data analysis procedure, and computational methods with advanced statistics were used for the configurational assignments of 1 and two pairs of inseparable epimers, 2/3 and 4/5. All compounds were evaluated for their anti-inflammatory, neuroprotective, and cytotoxic activities, with 1 showing weak anti-inflammatory activity (IC50 41.2 µM).

Design and synthesis of naphthalimide group-bearing thioglycosides as novel ß-N-acetylhexosaminidases inhibitors.

GH20 human ß-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these ß-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki = 0.91 µM against hsHexB; Ki > 100 µM against hOGA) and compound 15b (Ki = 3.76 µM against hOGA; Ki = 30.42 µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure-activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific ß-N-acetylhexosaminidase inhibitors.

Novel Uridine Glycoconjugates, Derivatives of 4-Aminophenyl 1-Thioglycosides, as Potential Antiviral Compounds.

A novel series of uridine glycoconjugates, derivatives of 4-aminophenyl 1-thioglycosides, was designed and synthesized. All compounds were evaluated in vitro for their antiviral activity against hepatitis C virus (HCV) and classical swine fever virus (CSFV), two important human and animal viral pathogens for which new or improved therapeutic options are needed. The antiviral activity of all synthesized compounds was confirmed using pseudo-plaque reduction assays in which a significant arrest of CSFV and HCV growth was observed in the presence of these compounds. Two of the synthesized compounds, 9 and 12, displayed a significant inhibitory effect on HCV and CSFV propagation with IC50 values of 4.9 and 13.5 µM for HCV and 4.2 and 4 µM for CSFV, respectively, with low cytotoxicity. Using various infection and replication models, we have shown that both compounds were able to significantly reduce viral genome replication by up to 90% with IC50 values in the low micromolar range. A structure activity analysis of the synthesized compounds showed that the high antiviral activity was attributed to the hydrophobicity of glycoconjugates and the introduction of elements capable to coordinate metal ions into the spacer connecting the sugar and uridine moiety, which can be useful in the development of new antiviral compounds in the future.

LX2761, a Sodium/Glucose Cotransporter 1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice.

LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated the effect of orally administered LX2761 on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower and plasma total glucagon-like peptide-1 (GLP-1) levels higher after an oral glucose challenge; these decreased glucose excursions persisted even when the glucose challenge occurred 15 hours after LX2761 dosing in ad lib-fed mice. Further, treating mice with LX2761 and the dipeptidyl-peptidase 4 inhibitor sitagliptin synergistically increased active GLP-1 levels, suggesting increased LX2761-mediated release of GLP-1 into the portal circulation. LX2761 also lowered postprandial glucose, fasting glucose, and hemoglobin A1C, and increased plasma total GLP-1, during long-term treatment of mice with either early- or late-onset streptozotocin-diabetes; in the late-onset cohort, LX2761 treatment improved survival. Mice and rats treated with LX2761 occasionally had diarrhea; this dose-dependent side effect decreased in severity and frequency over time, and LX2761 doses were identified that decreased postprandial glucose excursions without causing diarrhea. Further, the frequency of LX2761-associated diarrhea was greatly decreased in mice either by gradual dose escalation or by pretreatment with resistant starch 4, which is slowly digested to glucose in the colon, a process that primes the colon for glucose metabolism by selecting for glucose-fermenting bacterial species. These data suggest that clinical trials are warranted to determine if LX2761 doses and dosing strategies exist that provide improved glycemic control combined with adequate gastrointestinal tolerability in people living with diabetes.

Synthesis and biological evaluation of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thioglycosides.

In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a-4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a-4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated. Among the entire compounds lauric acid and myristic acid derivatives showed good and moderate antimicrobial activity. In case of cytotoxicity results of compounds 8a-8j and 9a-9j, the acetate protected short chain (C6:0, C8:0, C10:0) compounds and the free hydroxyl long chain saturated (C16:0, C18:0) and unsaturated (C18:1, C22:1) compounds exhibited good activity against different cancer cell lines. Further, the free hydroxyl compounds 9a, 9c-9j did not show any toxicity towards normal CHO-K1 cell line whereas acylated compounds 8a-8j exhibited toxicity.

Facile access to pseudo-thio-1,2-dimannoside, a new glycomimetic DC-SIGN antagonist.

The synthesis and conformational analysis of pseudo-thio-1,2-dimannoside are described. This molecule mimics mannobioside (Manα(1,2)Man) and is an analog of pseudo-1,2-dimannoside, with expected increased stability to enzymatic hydrolysis. A short and efficient synthesis was developed based on an epoxide ring-opening reaction by a mannosyl thiolate, generated in situ from the corresponding thioacetate. NMR-NOESY studies supported by MM3∗ calculations showed that the pseudo-thio-1,2-dimannoside shares the conformational behavior of the pseudo-1,2-dimannoside and is a structural mimic of the natural disaccharide. Its affinity for DC-SIGN was measured by SPR and found to be comparable to the corresponding O-linked analog, offering good opportunities for further developments.

Evaluation of the Mycobactericidal Effect of Thio-functionalized Carbohydrate Derivatives.

Sugars with heteroatoms other than oxygen have attained considerable importance in glycobiology and in drug design since they are often more stable in blood plasma due to their resistance to enzymes, such as glycosidases, phosphorylases and glycosyltransferases. The replacement of oxygen atoms in sugars with sulfur forms thio-sugars, which are potentially useful for the treatment of diabetes and some bacterial and viral infections. Here, we evaluated the antibacterial activity of thio-functionalized carbohydrate derivatives. A set of 21 compounds was screened against acid-fast Mycobacterium tuberculosis (Mtb), gram-negative Escherichia coli and gram-positive Staphylococcus aureus. The tested carbohydrate derivatives were most effective against tubercle bacilli, with as many as five compounds (thioglycoside 6, thiosemicarbazone 16A, thiosemicarbazone 20, aminothiadiazole 23, and thiazoline 26) inhibiting its growth with MIC50 ≤ 50 µM/CFU. Only two compounds (aminothiadiazole 23 and thiazoline 26) were able to inhibit the growth of E. coli at concentrations below 1 mM, and one of them, aminothiadiazole 23, inhibited the growth of S. aureus at a concentration ≤1 mM. The five compounds affecting the growth of mycobacteria were either thiodisaccharides (6, 16A, and 20) or thioglycosides (23 and 26). All of these compounds (6, 16A, 20, 23, and 26) were able to inhibit the growth of Mtb deposited within human macrophages. However, three of the five selected compounds (6, 23, and 26) exhibited relatively high cytotoxicity in mouse fibroblasts at micromolar concentrations. The selected thio-sugars are very promising compounds, thus making them candidates for further modifications that would decrease their cytotoxicity against eukaryotic cells without affecting their antimycobacterial potential.

Synthesis and Anticancer Activity of New 1-Thia-4-azaspiro[4.5]decane, Their Derived Thiazolopyrimidine and 1,3,4-Thiadiazole Thioglycosides.

New 1-thia-azaspiro[4.5]decane derivatives, their derived thiazolopyrimidine and 1,3,4-thiadiazole compounds were synthesized. The thioglycoside derivatives of the synthesized (1,3,4-thiadiazolyl)thiaazaspiro[4.5]decane and thiazolopyrimidinethione compounds were synthesized by glycosylation reactions using acetylated glycosyl bromides. The anticancer activity of synthesized compounds was studied against the cell culture of HepG-2 (human liver hepatocellular carcinoma), PC-3 (human prostate adenocarcinoma) and HCT116 (human colorectal carcinoma) cell lines and a number of compounds showed moderate to high inhibition activities.

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.

Synthesis and antimicrobial activity of new norbornyl system based oxadiazole thioglycosides and acyclic nucleoside analogs.

New sugar hydrazones linked to norbornyl ring system, their oxadiazole acyclic nucleoside analogs and the corresponding thioglycosides were synthesized. The synthesized compounds were tested for their antimicrobial activity and displayed different degrees of activities or inhibitory actions. Their oxadiazole acyclic nucleoside analogs and thioglycosides showed higher activities.

Photosensitizer-thioglycosides enhance photodynamic therapy by augmenting cellular uptake.

Photodynamic therapy (PDT) uses photosensitizing agents along with light to ablate tissue, including cancers. Such light-driven localized delivery of free-radical oxygen to kill target tissue depends on photosensitizer cell penetration efficacy. While the attachment of monosaccharides and disaccharides to photosensitizers has been shown to potentially provide improved photosensitizer delivery, the range of glycan entities tested thus far is limited. We sought to expand such knowledge by coupling N-acetylglucosamine (GlcNAc) to pyropheophorbides as thioglycosides, and then testing photosensitizer efficacy. To this end, GlcNAc was conjugated to both pyropheophorbide-a and methyl pyropheophorbide-a. Among the entities tested, the conjugation of N-acetylglucosamine to methyl pyropheophorbide-a ('PSe') as thioglycoside enhanced cell uptake both in the presence and absence of human serum proteins, relative to other compounds tested. The enhanced PSe penetrance into cells resulted in higher cell death upon illumination with 665 nm light. While acting as a potent photosensitizer, PSe did not affect cellular carbohydrate profiles. Overall, the study presents a new pyropheophorbide glycoconjugate with strong in vitro PDT efficacy.

Aromatic thioglycoside inhibitors against the virulence factor LecA from Pseudomonas aeruginosa.

Three small families of hydrolytically stable thioaryl glycosides were prepared as inhibitors of the LecA (PA-IL) virulence factor corresponding to the carbohydrate binding lectin from the bacterial pathogen Pseudomonas aeruginosa. The monosaccharidic arylthio ß-d-galactopyranosides served as a common template for the major series that was also substituted at the O-3 position. Arylthio disaccharides from lactose and from melibiose constituted the other two series members. In spite of the fact that the natural ligand for LecA is a glycolipid of the globotriaosylceramide having an α-d-galactopyranoside epitope, this study illustrated that the ß-d-galactopyranoside configuration having a hydrophobic aglycon could override the requirement toward the anomeric configuration of the natural sugar. The enzyme linked lectin assay together with isothermal titration microcalorimetry established that naphthyl 1-thio-ß-d-galactopyranoside () gave the best inhibition with an IC50 twenty-three times better than that of the reference methyl α-d-galactopyranoside. In addition it showed a KD of 6.3 µM which was ten times better than that of the reference compound. The X-ray crystal structure of LecA with was also obtained.

Thioglycosides Act as Metabolic Inhibitors of Bacterial Glycan Biosynthesis.

Glycans that coat the surface of bacteria are compelling antibiotic targets because they contain distinct monosaccharides that are linked to pathogenesis and are absent in human cells. Disrupting glycan biosynthesis presents a path to inhibiting the ability of a bacterium to infect the host. We previously demonstrated that O-glycosides act as metabolic inhibitors and disrupt bacterial glycan biosynthesis. Inspired by a recent study which showed that thioglycosides (S-glycosides) are 10 times more effective than O-glycosides at inhibiting glycan biosynthesis in mammalian cells, we crafted a panel of S-glycosides based on rare bacterial monosaccharides. The novel thioglycosides altered glycan biosynthesis and fitness in pathogenic bacteria but had no notable effect on glycosylation or growth in beneficial bacteria or mammalian cells. In contrast to findings in mammalian cells, S-glycosides and O-glycosides exhibited comparable potency in bacteria. However, S-glycosides exhibited enhanced selectivity relative to O-glycosides. These novel metabolic inhibitors will allow selective perturbation of the bacterial glycocalyx for functional studies and set the stage to expand our antibiotic arsenal.

Synthesis of novel pyridine and pyrimidine thioglycoside phosphoramidates for the treatment of COVID-19 and influenza A viruses.

A novel series of pyridine, cytosine, and uracil thioglycoside analogs (4a-i, 9a,b, and 13a,b, respectively) and their corresponding phosphoramidates (6a-I, 10a,b, and 14a,b, respectively) were synthesized and assessed for their antiviral inhibitory activities in a dual-pathogen screening protocol against SARS-CoV-2 and influenza A virus (IAV). MTT cytotoxicity (TC50) and plaque reduction assays were used to explore inhibition and cytotoxicity percentage values for H5N1 influenza virus strain and the half-maximal cytotoxic concentration (CC50) and inhibitory concentration (IC50) for SARS-CoV-2 virus. Most of the tested compounds demonstrated dose-dependent inhibition behavior. Both cytosine thioglycoside phosphoramidates 10a and 10b exhibited the most potent profiles with 83% and 86% inhibition at 0.25 µM concentration against H5N1 and IC50 values of 12.16 µM, 14.9 µM against SARS-CoV-2, respectively. Moreover, compounds 10a and 10b have been shown to have the highest selectivity index (SI) among all the tested compounds against SARS-CoV-2 with 28.2 and 26.9 values, respectively.