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PETER
NORRIS
Research@YSU
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Small
Molecule
Glycomimetics
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We
are mainly interested in synthetic heterocyclic chemistry, especially
synthesis using carbohydrates as precursors. Our current
projects include construction of
analogs of the aminosugars found in the defensive capsular
polysaccharide (CP) of Staphylococcus
aureus
(S.
aureus)
(Figure 1) that may be capable
of inhibiting CP construction and thus
serving as antibiotics. The three sugars found in the repeating units
of the most common strains of S.
aureus
(types 5 and 8) are the enantiomeric N-acetyl
D- and L-fucosamines
and N-acetyl-D-mannosamineuronic
acid. We
have recently solved the crystal structure of the N-acetyl-L-fucosamine
fragment (Figure 2). In
collaboration with Professor Diana Fagan in the Department of
Biological Sciences at YSU, we are able
to assay synthetic compounds as they are produced in order to study
their potential as inhibitors of CP biosynthesis. We have several
promising derivatives that have shown activity in suppressing capsule
growth.
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| C-C Bond-forming
Reactions on Sugars |
Derivatives
such as branched-chain sugars are important components of antibiotics
and the related C-glycosides
offer potential as non-hydrolyzable mimics of O-glycosides.
We are exploring the use of carbenoid insertion chemistry in this area
by building and decomposing sugar-linked diazo compounds, particularly
on furanose scaffolds. Metal-catalyzed diazo decomposition leads to
interesting products, including diastereomerically pure lactones
through C-H insertion products where the carbenoid bites back into the
carbohydrate framework (Figure 3).
We are using this chemistry in the
synthesis of several families of natural products including the
plakortones and canadensolides (Figure
4).
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| Method
Development for Parallel Synthesis |
A
long-term interest in the chemistry of nitrogen-containing functional
groups such as azides drives our efforts in the synthesis of novel
compounds. We have applied
so-called "click chemistry" methods to the parallel synthesis of
numerous glycosyl-1,2,3-triazoles using water as the solvent, as well
as using different phosphines in Staudinger-type chemistry to allow for
the synthesis of collections of related glycosyl amides, examples of
which have been shown to be biologically active.
We have also constructed novel carbohydrate oligomers using linkages
such as amides
and small heterocycles (Figure 5).
Both of these linkages
are proving amenable to the application of polymer- supported reagents
and the use of microwave heating to speed up reactions. Amide synthesis
is readily accomplished using various phosphines in a Staudinger-type
synthesis and should lead to diverse oligomeric structures
using parallel synthesis. These projects are particularly suitable for
undergraduates interested in gaining lab experience and some of our
recent
efforts in this area have been published (Carbohydr.
Res.
2006, 341,
1081-1090).
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