Chemical glycosylation [1,2] is a crucial step in any oligosaccharide [3] synthesis. [4,5] Among the different classes of commonly used glycosyl donors, [2] thioglycosides [6, 7] offer distinct advantages. Thioglycoside donors are relatively simple to prepare, are stable under various reactions for protectinggroup manipulations, and offer orthogonality in their activation in the presence of other glycosyl donors. [8] As a result, a wide variety of promoters have been developed for activation of these donors in the past 20 years: [2] from heavy metal-cation-based promoters (Hg II sulfate), [9] to the current halonium-based reagents [e.g., N-iodosuccinimide/trifluoromethane sulfonic acid (NIS/TfOH), [10] N-bromosuccinimide (NBS), [11] ICl or IBr/AgOTf, [12] etc.], alkylating reagents [methyl triflate (MeOTf)], [13] and organosulfur-based promoters [e.g., dimethyl(thiomethyl)sulfonium triflate (DMTST), [14] methylsulfenyl triflate (MeSOTf), [15] dimethyl disulfide/triflic anhydride (Me 2 S/Tf 2 O), [16] benzenesulfinylpiperidine/triflic anhydride (BSP/TTBP), [17] N-(phenylthio)-ecaprolactam-Tf 2 O, [18] etc.]. A recent method applies singleelectron transfer using ruthenium or iridium-containing catalysts that are active under visible light [19] to activate thioglycosides. Although these methods have been effective in carrying out a range of glycosylations, most of these still have a limited scope. Generally, these activations need excess amounts of promoters, [2,[9][10][11][12][13][14][15][16][17][18] or require a co-promoter to form the reactive intermediates. Moreover, present methods often require extremely low temperatures (< À20 8C) as a result of generating reactive intermediates. Some of the popular halonium-based promoters are challenging to use in the presence of alkenes, [20] because they tend to give various addition by-products, thereby ultimately resulting in the cleavage of the alkenyl moiety. These issues with solubility, undesired by-products, stability, or reagent handling are particularly problematic in the context of the development of robust automated protocols [21,22] for oligosaccharide synthesis. To circumvent some of these issues with current promoter systems, we herein report a straightforward method for the activation of thiopropylglycosides for coupling to various acceptors in good to excellent yields by utilizing a bismuth(V) compound without additional additives/copromoters.In lieu of the available promoters based on heavy-metal cations, bismuth presents interesting possibilities. Bismuth is a post-transition metal and like its neighboring metals such as mercury and lead, it is considered thiophilic as well as soft Lewis acidic. However, unlike Hg and Pb compounds, bismuth [23] is not only inexpensive, but also nontoxic. Unfortunately, despite its popularity as a treatment for digestive problems, [24] the synthetic utility of bismuth compounds remains relatively unexplored. However, the chemistry of this element [25] has gained considerable interest [26,27] over the past decade. [28] V...

Pseudomonas aeruginosa infections have reached a “critical” threat status making novel therapeutic approaches required.

We report the synthesis of a family of amphiphilic pentablock polymers with different cationic blocks and with controlled architectures as potential vaccine carriers for subunit vaccines. The temperature and pHdependent micellization and gelation of these pentablock copolymers can provide a depot for sustained protein and gene delivery. The amphiphilic central triblock promotes cellular endocytosis, good gene delivery and has been used effectively as a vaccine adjuvant. The pentablock copolymer outer blocks condense DNA spontaneously as a result of electrostatic interactions for sustained combinational therapy. This family of polymers with different cationic groups was evaluated based on DNA complexation-ability and cytotoxicity to select promising candidates as DNA-based subunit vaccine adjuvants. Modification of other polymer systems with carbohydrates like mannose has been shown to enhance immunogenicity by activating pattern recognition receptors on antigen presenting cells and increasing uptake in these cells. Here, we report the synthesis of a virus-mimicking pentablock copolymer vaccine platform by successful functionalization of these polymers with mannose through an azide-alkyne Huisgen cycloaddition. The synthesis of a mannoside with the alkyne linker was achieved by a recently reported bismuth(V)-mediated activation of a thioglycoside that proved to leave the alkyne intact. The carbohydrate modification was shown not to interfere with the ability of these virus-mimicking block copolymers to complex DNA, thereby making this family of modified materials promising candidates for DNA-based vaccine delivery. Disciplines

Bacterial histidine kinases (HKs) are quintessential regulatory enzymes found ubiquitously in bacteria. Apart from their regulatory roles, they are also involved in the production of virulence factors and conferring resistance to various antibiotics in pathogenic microbes. We have previously reported compounds that inhibit multiple HKs by targeting the conserved catalytic and ATP-binding (CA) domain. Herein, we conduct a detailed structure–activity relationship assessment of adenine-based inhibitors using biochemical and docking methods. These studies have resulted in several observations. First, interaction of an inhibitor’s amine group with the conserved active-site Asp is essential for activity and likely dictates its orientation in the binding pocket. Second, a N-NH-N triad in the inhibitor scaffold is highly preferred for binding to conserved Gly:Asp:Asn residues. Lastly, hydrophobic electron-withdrawing groups at several positions in the adenine core enhance potency. The selectivity of these inhibitors was tested against heat shock protein 90 (HSP90), which possesses a similar ATP-binding fold. We found that groups that target the ATP-lid portion of the catalytic domain, such as a six-membered ring, confer selectivity for HKs.

The mechanism of bismuth(V)-mediated thioglycoside activation was examined using reaction kinetics and quantum chemical reaction models. NMR experiments show an unusual nonlinear growth/decay curve for the glycosylation reaction. Further studies suggest an anomeric inversion of the β-glycoside donor to the α-donor during its activation, even in the presence of a neighboring 2-position acetate. Interestingly, in situ anomerization was not observed in the activation of an α-glycoside donor, and this anomer also showed faster reaction times and higher product diastereoselectivites. Density functional theory calculations identify the structure of the promoter triphenyl bismuth ditriflate, [Ph3Bi(OTf)2, 1], in solution and map out the energetics of its interactions with the two thioglycoside anomers. These calculations suggest that 1 must bind the thiopropyl arm to induce triflate loss. The computational analyses also show that, unlike most O-glycosides, the β- and α-donor S-glycosides are similar in energy. One energetically reasonable anomerization pathway of the donors is an SN1-like mechanism promoted by forming a bismuth-sulfonium adduct with the Lewis acidic Bi(V) for the formation of an oxacarbenium intermediate. Finally, the computed energy compensations needed to form these α vs β Bi adducts is a possible explanation for the differential reactivity of these donors.