Multigram-scale synthesis of l,d-heptoside using a Fleming-Tamao oxidation promoted by mercuric trifluoroacetate.

An efficient multigram-scale synthesis of methyl 2,3,4,6-tetra-O-benzyl-l-glycero-α-d-manno-heptopyranoside from methyl 2,3,4-tri-O-benzyl-α-d-mannopyranoside is reported. It involves a sequence of Swern oxidation, Grignard addition and Fleming-Tamao reactions. The resulting scaffold was used as a precursor to design a small library of clickable l-heptosides. This study shows that the use of mercuric bistrifluoroacetate is required both to accelerate and to cleanly perform the Fleming-Tamao oxidation, without side-reactions.

Eave Screening and Push-Pull Tactics to Reduce House Entry by Vectors of Malaria.

Long-lasting insecticidal nets and indoor residual spraying have contributed to a decline in malaria over the last decade, but progress is threatened by the development of physiological and behavioral resistance of mosquitoes against insecticides. Acknowledging the need for alternative vector control tools, we quantified the effects of eave screening in combination with a push-pull system based on the simultaneous use of a repellent (push) and attractant-baited traps (pull). Field experiments in western Kenya showed that eave screening, whether used in combination with an attractant-baited trap or not, was highly effective in reducing house entry by malaria mosquitoes. The magnitude of the effect varied for different mosquito species and between two experiments, but the reduction in house entry was always considerable (between 61% and 99%). The use of outdoor, attractant-baited traps alone did not have a significant impact on mosquito house entry but the high number of mosquitoes trapped outdoors indicates that attractant-baited traps could be used for removal trapping, which would enhance outdoor as well as indoor protection against mosquito bites. As eave screening was effective by itself, addition of a repellent was of limited value. Nevertheless, repellents may play a role in reducing outdoor malaria transmission in the peridomestic area.

The inhibition of liposaccharide heptosyltransferase WaaC with multivalent glycosylated fullerenes: a new mode of glycosyltransferase inhibition.

L,D-Heptosides (L-glycero-D-manno-heptopyranoses) are found in important bacterial glycolipids such as lipopolysaccharide (LPS), the biosynthesis of which is targeted for the development of novel antibacterial agents. This work describes the synthesis of a series of fullerene hexa-adducts bearing 12 copies of peripheral sugars displaying the mannopyranose core structure of bacterial L,D-heptoside. The multimers were assembled through an efficient copper-catalyzed alkyne-azide cycloaddition reaction as the final step. The final fullerene sugar balls were assayed as inhibitors of heptosyltransferase WaaC, the glycosyltransferase catalyzing the incorporation of the first L-heptose into LPS. Interestingly, the inhibition of the final molecules was found in the low micromolar range (IC(50) =7-45 µM), whereas the corresponding monomeric glycosides displayed high micromolar to low millimolar inhibition levels (IC(50) always above 400 µM). When evaluated on a "per-sugar" basis, these inhibition data showed that, in each case, the average affinity of a single glycoside of the fullerenes towards WaaC was significantly enhanced when displayed as a multimer, thus demonstrating an unexpected multivalent effect. To date, such a multivalent mode of inhibition had never been evidenced with glycosyltransferases.

Systematic synthesis of inhibitors of the two first enzymes of the bacterial heptose biosynthetic pathway: towards antivirulence molecules targeting lipopolysaccharide biosynthesis.

L-Heptoses (L-glycero-D-manno-heptopyranoses) are constituents of the inner core of lipolysaccharide (LPS), a molecule playing key roles in the mortality of many infectious diseases as well as in the virulence of many human pathogens. The inhibition of the first enzymes of the bacterial heptose biosynthetic pathway is an almost unexplored field to date although it appears to be a very novel way for the development of antivirulence drugs. We report the synthesis of a series of D-glycero-D-manno-heptopyranose 7-phosphate (H7P) analogues and their inhibition properties against the isomerase GmhA and the the kinase HldE, the two first enzymes of the bacterial heptose biosynthetic pathway. The heptose structures have been modified at the 1-, 2-, 6- and 7-positions to probe the importance of the key structural features of H7P that allow a tight binding to the target enzymes; H7P being the product of GmhA and the substrate of HldE, the second objective was to find structures that could simultaneously inhibit both enzymes. We found that GmhA and HldE were extremely sensitive to structural modifications at the 6- and 7- positions of the heptose scaffold. To our surprise, the epimeric analogue of H7P displaying a D-glucopyranose configuration was found to be the best inhibitor of both enzymes but also the only molecule of this series that could inhibit GmhA (IC(50)=34 µM) and HldE (IC(50)=9.4 µM) in the low micromolar range. Noteworthy, this study describes the first inhibitors of GmhA ever reported, and paves the way to the design of a second generation of molecules targeting the bacterial virulence.

The functional valency of dodecamannosylated fullerenes with Escherichia coli FimH--towards novel bacterial antiadhesives.

Fullerene hexakis-adducts bearing 12 peripheral mannose moieties have been prepared by grafting sugar derivatives onto the fullerene core and assayed as inhibitors of FimH, a bacterial adhesin, using isothermal titration calorimetry, surface plasmon resonance and hemagglutination assays.

Fullerene sugar balls.

Fullerene hexakis-adducts bearing 12 peripheral carbohydrate moieties have been prepared by grafting sugar derivatives onto the fullerene core through the copper mediated Huisgen 1,3-dipolar cycloaddition of azides and alkynes.

Phenyl 2,3,4-tri-O-benzyl-1-thio-α-d-mannopyran-oside monohydrate.

In the title compound, C(33)H(34)O(5)S·H(2)O, the mannopyran-oside ring adopts a chair conformation with the 2-α-thio-phenyl group occupying an axial position. One of the pendant benzyl groups is disordered over two sets of sites in a 0.5:0.5 ratio. In the crystal, the water mol-ecule makes two O-H⋯O hydrogen bonds to an adjacent sugar mol-ecule with the O atoms of the primary alcohol and ether groups acting as acceptors. At the same time, the OH group of the sugar makes a hydrogen bond to a water mol-ecule.

Stereoselective glycal fluorophosphorylation: synthesis of ADP-2-fluoroheptose, an inhibitor of the LPS biosynthesis.

Heptosides are found in important bacterial glycolipids such as lipopolysaccharide (LPS), the biosynthesis of which is targeted for the development of novel antibacterial agents. This work describes the synthesis of a fluorinated analogue of ADP-L-glycero-beta-D-manno-heptopyranose, the donor substrate of the heptosyl transferase WaaC, which catalyzes the incorporation of this carbohydrate into LPS. Synthetically, the key step for the preparation of ADP-2F-heptose is the simultaneous and stereoselective installation of both the fluorine atom at C-2 and the phosphoryl group at C-1 through a selectfluor-mediated (selectfluor=1-chloromethyl-4-fluorodiazoniabicyclo[2.2.2]octane bis(triflate)) electrophilic addition/nucleophilic substitution involving a heptosylglycal. Therefore, we detail in this article 1) the stereoselective preparation of the key intermediates heptosylglycals, 2) the development of a new fluorophosphorylation procedure allowing an excellent beta-gluco stereoselectivity with "all-equatorial" glycals, 3) the synthesis of the target ADP-2F-heptose, and 4) some comments on the contacts observed between the fluorine atom of the final molecule and the protein in the crystallographic structure of heptosyltransferase WaaC.