Straightforward synthesis of the hexasaccharide repeating unit of the O-specific polysaccharide of Salmonella arizonae O62.

A straightforward synthesis of the hexasaccharide repeating unit of the O-specific polysaccharide of Salmonella arizonae O62 was achieved in very good yield applying sequential glycosylation strategy. Successful regioselective glycosylation of the di-hydroxylated L-rhamnose moiety allowed achieving the desired compound in minimum number of synthetic steps. TEMPO catalyzed and [bis(acetoxy)iodo]benzene (BAIB) mediated late stage regioselective oxidation of a primary hydroxyl group into carboxylic acid was achieved in the hexasaccharide derivative. The glycosylation steps were high yielding with high stereochemical outcome. The desired hexasaccharide was obtained in 7% over all yield in fourteen steps starting from suitably functionalized monosaccharide intermediates.

Syntheses of Salmonella Paratyphi†A Associated Oligosaccharide Antigens and Development towards Anti-Paratyphoid Fever Vaccines.

With the emergence of multidrug resistant Salmonella strains, the development of anti-Salmonella vaccines is an important task. Currently there are no approved vaccines against Salmonella Paratyphi A, the leading cause of paratyphoid fever. To fill this gap, oligosaccharides corresponding to the O-polysaccharide repeating units from the surface of Salmonella Paratyphi A have been synthesized through convergent stereoselective glycosylations. The synthetic glycan antigen was conjugated with a powerful immunogenic carrier system, the bacteriophage Qß. The resulting construct was able to elicit strong and long-lasting anti-glycan IgG antibody responses, which were highly selective toward Salmonella Paratyphi A associated glycans. The availability of well-defined glycan antigen enabled the determination that one repeating unit of the polysaccharide is sufficient to induce protective antibodies, and the paratose residue and/or the O-acetyl modifications on the backbone are important for recognition by antibodies elicited by a Qß-tetrasaccharide conjugate. Immune sera provided excellent protection to mice from lethal challenge with Salmonella Paratyphi A, highlighting the potential of the synthetic glycan-based vaccine.

Straightforward synthesis of the pentasaccharide repeating unit of the cell wall O-antigen of Escherichia coli O43 strain.

A concise synthetic strategy has been developed for the synthesis of the pentasaccharide repeating unit of the cell wall O-antigen of Escherichia coli O43 strain involving stereoselective ß-D-mannosylation and α-L-fucosylation using corresponding trichloroacetimidate intermediates and perchloric acid supported over silica (HClO4-SiO2) as glycosylation promoter. The yield and stereoselectivity of the glycosylations were very good.

Anti-cancer potential of (1,2-dihydronaphtho[2,1-b]furan-2-yl)methanone derivatives.

A series of 1,2-dihydronaphtho[2,1-b]furan derivatives were synthesized by cyclizing 1-(aryl/alkyl(arylthio)methyl)-naphthalen-2-ol and pyridinium bromides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in very good yield. The synthesized compounds were evaluated for their anti-proliferative potential against human triple negative MDA-MB-468 and MCF-7 breast cancer cells and non-cancerous WI-38 cells (lung fibroblast cell) using MTT experiments. Among 21 synthesized compounds, three compounds (3a, 3b and 3 s) showed promising anti-cancer potential and compound 3b was found to have best anti-proliferative activities based on the results of several biochemical and microscopic experiments.

Convenient synthesis of the pentasaccharide repeating unit corresponding to the cell wall O-antigen of Escherichia albertii O4.

A straightforward sequential synthetic strategy has been developed for the synthesis of a pentasaccharide repeating unit corresponding to the cell wall O-antigen of the Escherichia albertii O4 strain in very good yield with the desired configuration at the glycosidic linkages using thioglycosides and trichloroacetimidate derivatives as glycosyl donors and perchloric acid supported over silica (HClO4/SiO2) as a solid supported protic acid glycosyl activator. The expected configuration at the glycosidic linkages was achieved using a reasonable selection of protecting groups in the manosaccharide intermediates.

Synthesis of the tetrasaccharide repeating unit of the O-specific polysaccharide of Azospirillum doebereinerae type strain GSF71T using linear and one-pot iterative glycosylations.

A straightforward synthetic strategy was developed for the synthesis of the tetrasaccharide repeating unit corresponding to the O-specific polysaccharide of Azospirillum doebereinerae type strain GSF71T in a very good yield adopting sequential glycosylation followed by removal of the p-methoxybenzyl (PMB) group in the same pot. Further, the synthetic strategy was modified by carrying out three stereoselective iterative glycosylations followed by in situ removal of the PMB group in one pot. The stereochemical outcome of the newly formed glycosidic linkages was excellent using thioglycoside derivatives as glycosyl donors and a combination of N-iodosuccinimide (NIS) and perchloric acid supported on silica (HClO4-SiO2) as the glycosyl activator.

Homologs from sulfur oxidation (Sox) and methanol dehydrogenation (Xox) enzyme systems collaborate to give rise to a novel pathway of chemolithotrophic tetrathionate oxidation.

The SoxXAYZB(CD)2 -mediated pathway of bacterial sulfur-chemolithotrophy explains the oxidation of thiosulfate, sulfide, sulfur and sulfite but not tetrathionate. Advenella kashmirensis, which oxidizes tetrathionate to sulfate, besides forming it as an intermediate during thiosulfate oxidation, possesses a soxCDYZAXOB operon. Knock-out mutations proved that only SoxBCD is involved in A. kashmirensis tetrathionate oxidation, whereas thiosulfate-to-tetrathionate conversion is Sox independent. Expression of two glutathione metabolism-related proteins increased under chemolithotrophic conditions, as compared to the chemoorganotrophic one. Substrate-dependent oxygen consumption pattern of whole cells, and sulfur-oxidizing enzyme activities of cell-free extracts, measured in the presence/absence of thiol inhibitors/glutathione, corroborated glutathione involvement in tetrathionate oxidation. Furthermore, proteome analyses detected a sulfite:acceptor oxidoreductase (SorAB) exclusively under chemolithotrophic conditions, while expression of a methanol dehydrogenase (XoxF) homolog, subsequently named thiol dehydrotransferase (ThdT), was found to increase 3- and 10-fold during thiosulfate-to-tetrathionate conversion and tetrathionate oxidation respectively. A thdT knock-out mutant did not oxidize tetrathionate but converted half of the supplied 40 mM S-thiosulfate to tetrathionate. Knock-out of another thiosulfate dehydrogenase (tsdA) gene proved that both ThdT and TsdA individually converted ∼ 20 mM S-thiosulfate to tetrathionate. The overexpressed and isolated ThdT protein exhibited PQQ-dependent thiosulfate dehydrogenation, whereas its PQQ-independent thiol transfer activity involving tetrathionate and glutathione potentially produced a glutathione:sulfodisulfane adduct and sulfite. SoxBCD and SorAB were hypothesized to oxidize the aforesaid adduct and sulfite respectively.

Organocatalyzed preparation of 1,4,5-trisubstituted-glycosyl-1,2,3-triazole derivatives.

Organocatalytic coupling of glycosyl azides with enolates of active ketones and esters through azide-enolate [3 + 2] cycloaddition in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) furnished 1,4,5-trisubstituted-glycosyl-1,2,3-triazole derivatives in excellent yield. The reaction condition is simple and can be scaled-up. Graphical abstract Coupling of glycosyl azides with active ketones through azide-enolate [3 + 2] cycloaddition in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) furnished 1,4,5-trisubstituted-glycosyl-1,2,3-triazole derivatives in excellent yield.

Anti-cancer potential of novel glycosylated 1,4-substituted triazolylchalcone derivatives.

A series of glycosylated 1,4-substituted triazolyl chalcone derivatives (8a-f and 14a-r) were synthesized in high yield using 1,3-cycloaddition (Click chemistry) of d-glucosyl azides with a variety of propargylated chalcone derivatives followed by de-O-acetylation. The synthesized compounds were evaluated for their cytotoxic potential against the human breast carcinoma cell lines and non-cancerous cells. The MTT assay identified three promising cytotoxic compounds (14c, 14i and 14l) and further biochemical and microscopic studies were carried out with the best compound 14i among the active compounds.

Influence of remote functional groups towards the formation of 1,2-cis glycosides: special emphasis on ß-mannosylation.

A convenient straightforward method has been developed for 1,2-cis glycosylation and ß-mannosylation in excellent yields using glycosyl donors having a 4,6-O-benzylidene acetal together with a p-methoxybenzyl (PMB) or 2-naphthylmethyl (NAP) group at the C-3 position under standard glycosylation conditions.

Glycosyl selenoacetates: versatile building blocks for the preparation of stereoselective selenoglycosides and selenium linked disaccharides.

Glycosyl selenoacetate derivatives were prepared by the treatment of glycosyl halide with potassium selenocyanate followed by acetylation of in situ generated glycosyl selenols in one pot. A variety of selenoglycosides and selenium linked disaccharide derivatives were prepared in very good to excellent yields using glycosyl selenoacetates as stable building blocks under mild reaction conditions.

Influence of autophagy, apoptosis and their interplay in filaricidal activity of C-cinnamoyl glycosides.

The present work aims to explore the mechanism of action of C-cinnamoyl glycoside as an antifilarial agent against the bovine filarial nematode Setaria cervi. Both apoptosis and autophagy programmed cell death pathways play a significant role in parasitic death. The generation of reactive oxygen species, alteration of the level of antioxidant components and disruption of mitochondrial membrane potential may be the causative factors that drive the parasitic death. Monitoring of autophagic flux via the formation of autophagosome and autophagolysosome was detected via CYTO ID dye. The expression profiling of both apoptotic and autophagic marker proteins strongly support the initial findings of these two cell death processes. The increased interaction of pro-autophagic protein Beclin1 with BCL-2 may promote apoptotic pathway by suppressing anti-apoptotic protein BCL-2 from its function. This in turn partially restrains the autophagic pathway by engaging Beclin1 in the complex. But overall positive increment in autophagic flux was observed. Dynamic interaction and regulative balance of these two critical cellular pathways play a decisive role in controlling disease pathogenesis. Therefore, the present experimental work may prosper the chance for C-cinnamoyl glycosides to become a potential antifilarial therapeutic in the upcoming day after detail in vivo study and proper clinical trial.

Natural product inspired allicin analogs as novel anti-cancer agents.

A series of novel analogs of Allicin (S-allyl prop-2-ene-1-sulfinothioate) present in garlic has been synthesized in high yield. Synthesized 23 compounds were evaluated against different breast cancer cells (MDA-MB-468 and MCF-7) and non-cancer cells (WI38). Four compounds (3f, 3h, 3m and 3u) showed significant cytotoxicity against cancer cells whereas nontoxic to the normal cells. Based on the LD50 values and selectivity index (SI), compound 3h (S-p-methoxybenzyl (p-methoxyphenyl)methanesulfinothioate) was considered as most promising anticancer agent amongst the above three compounds. Further bio-chemical studies confirmed that compound 3h promotes ROS generation, changes in mitochondrial permeability transition and induced caspase mediated DNA damage and apoptosis.

Convergent synthesis of the pentasaccharide repeating unit of the biofilms produced by Klebsiella pneumoniae.

A pentasaccharide repeating unit containing α-linked D-glucuronic acid, ß-linked D-mannose, corresponding to the repeating unit of biofilms produced by Klebsiella pneumoniae, has been synthesized using a stereoselective [2 + 3] convergent glycosylation strategy. The ß-D-mannosidic moiety has been synthesized using a D-mannose-derived thioglycoside by a two-step activation process. Late stage TEMPO-mediated oxidation of the pentasaccharide derivative using phase-transfer reaction conditions furnished the target compound in satisfactory yield.

Expedient synthesis of the pentasaccharide repeating unit of the O-antigen of Escherichia coli O86 and its conformational analysis.

Synthesis of the pentasaccharide with a 2-aminoethyl linker attached to the reducing end corresponding to the cell wall O-antigen of Escherichia coli O86 strain is reported. The synthetic strategy involves sequential glycosylation of suitably protected monosaccharide intermediates under similar glycosylation reaction conditions. Thioglycosides have been used as glycosyl donor throughout the synthetic strategy. Conformational analysis of the synthesized pentasaccharide has been carried out using 2D ROESY NMR spectral analysis and all atom explicit molecular dynamics (MD) simulation technique. Graphical abstract Facile synthesis of the pentasaccharide with a 2-aminoethyl linker attached to the reducing end corresponding to the cell wall O-antigen of Escherichia coli O86 strain is reported. Conformational analysis of the synthesized pentasaccharide has been carried out using 2D ROESY NMR spectral analysis and all atom explicit molecular dynamics (MD) simulation technique.

Synthesis and evaluation of triazole linked glycosylated 18ß-glycyrrhetinic acid derivatives as anticancer agents.

A series of glycosyl triazol linked 18ß-glycyrrhetinic acid (GA) derivatives have been synthesized using 1,3-dipolar cycloaddition reaction of per-O-acetylated glycosyl azide derivatives (4a-h) with propargyl ester of 18ß-glycyrrhetinic acid (GA) (2 and 3) following the concept of 'Click chemistry'. The synthesized triazole derivatives were de-O-acetylated to furnish compounds (7a-h and 8a-c) with free hydroxyl groups in the carbohydrate moieties, which were evaluated for their anticancer potential against human cervical cancer cells (HeLa) and normal kidney epithelial (NKE) cells. GA (1), compound 7d, compound 7g and compound 8c showed promising anticancer activities.

Convergent synthesis of a tetrasaccharide repeating unit of the O-specific polysaccharide from the cell wall lipopolysaccharide of Azospirillum brasilense strain Sp7.

A straightforward convergent synthesis has been carried out for the tetrasaccharide repeating unit of the O-specific cell wall lipopolysaccharide of the strain Sp7 of Azospirillum brasilense. The target tetrasaccharide has been synthesized from suitably protected monosaccharide intermediates in 42% overall yield in seven steps by using a [2 + 2] block glycosylation approach.

Convergent synthesis of the pentasaccharide repeating unit corresponding to the cell wall O-polysaccharide of Salmonella milwaukee (group U) O:43 strain.

Synthesis of the pentasaccharide repeating unit of the cell O-polysaccharide produced by Salmonella milwaukee O:43 strain (group U) has been achieved in very good yield adopting a convergent stereoselective [3 + 2] block glycosylation strategy. Thioglycosides and glycosyl trichloroacetimidate derivative were used as glycosyl donors in the presence of a combination of N-iodosuccinimide (NIS) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) as thiophilic activator and TMSOTf as trichloroacetimidate activator respectively. The stereochemical outcome of all glycosylation reactions was excellent.