115520-89-3Relevant academic research and scientific papers
Systematic synthesis of inhibitors of the two first enzymes of the bacterial heptose biosynthetic pathway: Towards antivirulence molecules targeting lipopolysaccharide biosynthesis
Durka, Maxime,Tikad, Abdellatif,Périon, Régis,Bosco, Michael,Andaloussi, Mounir,Floquet, Stéphanie,Malacain, Elodie,Moreau, Fran?ois,Oxoby, Mayalen,Gerusz, Vincent,Vincent, Stéphane P.
supporting information; experimental part, p. 11305 - 11313 (2011/10/19)
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 (IC50=34 μM) and HldE (IC50=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. Copyright
Higher-Carbon Sugars. Part 13. The Catalytic Osmylation of Some α,β-Unsaturated Octuronic Acid Derivatives and a Synthesis of (meso)-threo-gluco-Octitol
Barnes, John C.,Brimacombe, John S.,McDonald, Graeme
, p. 1483 - 1489 (2007/10/02)
In compliance with Kishi's empirical rule, catalytic osmylation of methyl uronate (6) produced a mixture of methyl (methyl 2,3,4,-tri-O-benzyl-β-L-threo-D-gluco-octopyranosid)uronate
Higher-carbon Sugars. Part 12. The Synthesis of New Octitols from D-Glucose and D-Mannose via the Osmylation of Unsaturated Precursors
Barnes, John C.,Brimacombe, John S.,Kabir, Abul K. M. S.,Weakley, Timothy J. R.
, p. 3391 - 3398 (2007/10/02)
Catalytic osmylation of methyl (E)-2,3,4-tri-O-benzyl-6,7-dideoxy-α-D-gluco-oct-6-enopyranoside (8) produced a mixture of methyl 2,3,4-tri-O-benzyl-β-L-threo-D-gluco-octopyranoside (9) and the corresponding α-D-threo-D-gluco isomer (10) in the ratio ca. 3
ON THE STEREOCHEMISTRY OF OSMIUM TETRAOXIDE OXIDATIONS OF ALLYLIC SYSTEMS USED IN THE SYNTHESIS OF HIGHER-CARBON SUGARS
Brimacombe, John S.,Kabir, Abul K. M. S.
, p. 21 - 30 (2007/10/02)
The stereochemistry of the major osmylation products of carbohydrate-based allylic alcohols can usually be predicted by application of Kishi's empirical rule.In particular, the addition of OsO4 can be formulated as taking place in the more abundant conformation on the surface anti to a pyranose or furanose ring-oxygen atom located at a stereocentre adjacent to the olefinic linkage.Exceptions to Kishi's empirical rule for osmylation are sometimes encountered with conjugated carbonyl compounds.
