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Carbohydrate-protein interactions are involved in a myriad of biological processes. Thus, glycomimetics have arisen as one of the most promising synthetic targets to that end. Within the broad variety of glycomimetics, thiodisaccharides have proven to be excellent tools to study these processes, and even more, some of them unveiled interesting biological activities. This review brings together research made on the introduction of N-acetylhexosamine residues into thiodisaccharides to date, passing through classic substitution (as SN 2, thioglycosylation and ring-opening reactions) and addition (as thiol-ene coupling and Michael-type additions) reactions. Recent and interesting developments regarding addition reactions to vinyl azides, cross-coupling reactions and novel chemoenzymatic methods are also discussed.

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One of the main factors limiting the effectiveness of many drugs is the difficulty of their delivery to their target site in the cell and achieving the desired therapeutic dose. Moreover, the accumulation of the drug in healthy tissue can lead to serious side effects. The way to improve the selectivity of a drug to the cancer cells seems to be its conjugation with a sugar molecule, which should facilitate its selective transport through GLUT transporters (glucose transporters), whose overexpression is seen in some types of cancer. This was the idea behind the synthesis of 8-hydroxyquinoline (8-HQ) derivative glycoconjugates, for which 1-thiosugar derivatives were used as sugar moiety donors. It was expected that the introduction of a sulfur atom instead of an oxygen atom into the anomeric position of the sugar would increase the stability of the obtained glycoconjugates against untimely hydrolytic cleavage. The anticancer activity of new compounds was determined based on the results of the MTT cytotoxicity tests. Because of the assumption that the activity of this type of compounds was based on metal ion chelation, the effect of the addition of copper ions on cell proliferation was tested for some of them. It turned out that cancer cells treated with glycoconjugates in the presence of Cu2+ had a much slower growth rate compared to cells treated with free glycoconjugates in the absence of copper. The highest cytotoxic activity of the compounds was observed against the MCF-7 cell line.

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We have recently found that selected thio-disaccharides possess bactericidal effects against Mycobacterium tuberculosis but not against Escherichia coli or Staphylococcus aureus. Here, we selected spontaneous mutants displaying resistance against the investigated thio-glycoside. According to next-generation sequencing, four of six analyzed mutants which were resistant to high concentrations of the tested chemical carried nonsynonymous mutations in the gene encoding the PPE51 protein. The complementation of these mutants with an intact ppe51 gene returned their sensitivity to the wild-type level. The uptake of tritiated thio-glycoside was significantly more abundant in wild-type Mycobacterium tuberculosis compared to the strain carrying the mutated ppe51 gene. The ppe51 mutations or CRISPR-Cas9-mediated downregulation of PPE51 expression affected the growth of mutant strains on minimal media supplemented with disaccharides (maltose or lactose) but not with glycerol or glucose as the sole carbon and energy source. Taking the above into account, we postulate that PPE51 participates in the uptake of disaccharides by tubercle bacilli.

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We introduce here a new fluorescent derivative of 1-thio-ß-N-acetylglucosamine linked to a pyrene system through a triazolylpentyl spacer, designed to self-assemble into a multivalent glycocluster. The synthesis was achieved by efficient CuAAC click reaction between a pyrene functionalized with an azide group and a suitable alkynyl thiomonosaccharide. Spectroscopic studies by fluorometry indicated that the self-assembly in aqueous medium is modulated by concentration and pH changes, the latter due to the presence of the amino group close to the π system. Circular dichroism experiments revealed a moderate positive signal, suggesting that the pyrene-thioGlcNAc conjugate can aggregate into a chiral supramolecular assembly. The sugar moiety showed to specifically and reversibly interact with the wheat germ agglutinin, a fact that was demonstrated by turbidity assay. SEM microscopy of a lyophilized solution at pH 10 revealed a fibrillar morphology compatible with the presence of tubular micelles, whereas crystalline and amorphous solids are formed at lower pHs.

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O-Linked glycosylation of serine and threonine residues of nucleocytoplasmic proteins with N-acetylglucosamine (O-GlcNAc) residues is catalyzed by O-GlcNAc transferase (OGT). O-GlcNAc is conserved within mammals and is implicated in a wide range of physiological processes. Herein, we describe metabolic precursor inhibitors of OGT suitable for use both in cells and in vivo in mice. These 5-thiosugar analogues of N-acetylglucosamine are assimilated through a convergent metabolic pathway, most likely involving N-acetylglucosamine-6-phosphate de-N-acetylase (NAGA), to generate a common OGT inhibitor within cells. We show that of these inhibitors, 2-deoxy-2-N-hexanamide-5-thio-d-glucopyranoside (5SGlcNHex) acts in vivo to induce dose- and time-dependent decreases in O-GlcNAc levels in various tissues. Decreased O-GlcNAc correlates, both in vitro within adipocytes and in vivo within mice, with lower levels of the transcription factor Sp1 and the satiety-inducing hormone leptin, thus revealing a link between decreased O-GlcNAc levels and nutrient sensing in peripheral tissues of mammals.

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Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or ß-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or ß-mono-, di-, and poly-thiosugar derivatives to efficiently synthesize a series of α- or ß-N,S-bis-glycosyl quinolin-2-ones, which are difficult to synthesize by classical methods.

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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.

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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.

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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.

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The [4-thio]-S-ribosylhomocysteine (SRH) analogs containing substitution of a sulfur atom for the endocyclic oxygen were synthesized by coupling of the 4-thioribose substrates with a thiolate generated from the protected homocysteine. Coupling of the protected 1-deoxy-5-O-mesyl-S-oxo-4-thio-D-ribofuranose with homocysteinate salt gave the C4 epimers of [4-thio]-SRH at the sulfoxide oxidation level lacking a hydroxyl group at anomeric carbon. Treatment of these sulfoxides with BF3⋅Et2O/NaI affected simultaneous reduction to sulfide and global deprotection affording 1-deoxy-4-thio-SRH analog. Treatment of the protected 1-deoxy-S-oxo-4-thio-D-ribofuranose sulfoxide with DAST/SbCl3 resulted in the fluoro-Pummerer rearrangement to give 4-thio-ß-D-ribofuranosyl fluoride. Mesylation of the latter at 5-hydroxyl position followed by coupling with homocysteinate salt and subsequent global deprotection with trifluoroacetic acid afforded [4-thio]-SRH thiohemiacetal.

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A general and efficient protocol for the palladium-catalyzed functionalization of mono- and polyglycosyl thiols by using the palladacycle precatalyst G3-XantPhos was developed. The C-S bond-forming reaction was achieved rapidly at room temperature with various functionalized (hetero)aryl-, alkenyl-, and alkynyl halides. The functional group tolerance on the electrophilic partner is typically high and anomer selectivities of thioglycosides are high in all cases studied. New sulfur nucleophiles such as thiophenols, alkythiols, and thioaminoacids (cysteine) were also successfully coupled to lead to the most general and practical method yet reported for the functionalization of thiols.

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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.

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INTRODUCTION: In the recent decades, the interest on glycosidases has dramatically increased, mainly because these enzymes play a key role in many biological processes. The importance of these enzymes is also reflected by a number of diseases, which result from the lack or dysfunction of a given glycosidase, as well as by the use of glycosidase inhibitors in the treatment of metabolic disorders or viral infections. 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, carbasugars, thiosugars and other non-glycosidic compounds will be discussed and special attention will be given to the ones that are currently used clinically. AREAS COVERED: 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 relevant research, patents and patent applications filed in the past years on the field. EXPERT OPINION: Since the glycosidase inhibitors are involved in several chronic diseases and possibly pandemic, the pharmaceutical research toward developing new generations of these molecules is very important to public health in the world. The unique combination of these compounds - for example, they share many properties with natural carbohydrates and also possess distinct specific characteristics - makes them precious for pharmaceutical companies in an attempt to search for potential new drugs. Currently, the most promising compounds are the iminosugars and thiosugars due to their better oral bioavailability.

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Diverse functionalized representatives of various classes of sugars, such as thio-, anhydro-, and sulfamido-sugars and myo-inositol oxide, were synthesized and assessed for cytotoxicity against human cancer cell lines (A549, LoVo, MCF-7 and HeLa). The inositol oxide (4) was more active against MCF-7 cells (i.e., an estrogen-dependent breast cancer line), whereas all 3 sulfur-containing compounds 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.

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Methyl 5'-thio-α-isomaltoside (1), which contains the ring-sulfur analogue of the nonreducing glucoside of isomaltose, was synthesized from gentiobiose through a novel ring opening-recyclization approach. The nonreducing glucoside of per-O-benzylated phenyl 1-thio-ß-gentiobioside underwent O-5'-C-1' bond cleavage with dimethyl-boron bromide and thiolacetic acid to give the acyclic monothioacetal 4 with the 1-thioglucopyranoside at the reducing end intact. The HO-5' group in 4 was inverted by a standard oxidation-reduction process with good efficiency. Recyclization under Mitsunobu condition allowed C-5'-S-1' bond formation with inversion of configuration at C-5', to give 1 after functional group interconversion. TLC analysis showed that 1, unlike isomaltose, was not hydrolyzed by glucoamylase from Rhizopus niveus. A fluorometric assay confirmed that the dissociation constant (Kd ) for 1 with the enzyme was 39 mM at 20°C, which is comparable with that for isomaltose. A binding assay involving fluorescence titration of the enzyme-1 complex with gluconolactone indicated that the disaccharide 1 was bound to the catalytic and noncatalytic subsites. Since isomaltose is known to bind only to the noncatalytic subsites, this result indicates a relatively high affinity of the 5-thioglucose moiety for the catalytic subsite.