Chemistry Reference
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future, combinatorial biosynthesis approaches, such as the exchange of biosynthesis
genes of glycopeptide producers, are expected to be developed. In the following sec-
tions, semisynthetic SAR studies and rational semisynthetic concepts for the develop-
ment of novel glycopeptides will be presented.
2.8.1
Modifications of Glycopeptide Antibiotics
2.8.1.1 Deglycosylated Glycopeptide Derivatives
The complete or sequential deglycosylation of glycopeptides is one basic reaction
to dissect contributions of glycosyl residues to the antibiotic activity. Vancomycin
and teicoplanin can be converted to desvancosaminyl vancomycin in trifluoroacetic
acid (TFA) at
15
C and completely deglycosylated in TFA at 50
C according to
previously published procedures.
100-102
Using TFA-based protocols, considerable
loss of glycopeptide has been observed, and therefore, less harsh procedures
have been developed with an HF-mediated cleavage of carbohydrate residues.
103
Previous publications on the dimerization of glycopeptide antibiotics
(see Section 2.3) have shown that glycosylation represents more than merely the
enhancement of water solubility and pharmacological properties. An important
finding in this context is that the absence of amino sugars leads to a reduced dimer-
ization and in most cases to a reduced antibiotic activity. Selectively deglycosylated
teicoplanines have also been investigated for their antibiotic activity.
104
As in vitro
assays show, only slight variations exist in the activity against certain bacterial
strains for these derivatives. Most significantly, the loss of the N-acylglucosamine
moiety has a less favorable influence on the pharmacokinetic performance. In
general, the partially or fully deglycosylated derivatives commonly serve as starting
material for other carbohydrate modifications or substitution reactions by chemical
or enzymatic approaches.
2.8.1.2 Glycosylation of Glycopeptide Derivatives
For the substitution of the carbohydrate portion of glycopeptides or for the coupling
of novel glycosyl residues, the corresponding aglycones serve as starting materials
for semisynthetic modifications. To introduce glycosylations by chemical methods,
in one example, all phenolic groups and the C-terminus were allylated, followed by
the protection of the N-terminus with Alloc.
105,106
Remaining hydroxy groups were
acetylated, and the phenolic side chain of
4
Hpg, which was previously protected,
was then glycosylated with sulfoxide chemistry to yield vancomycines.
A similar example, which demonstrates the feasability of aglycon glycosylation
on solid-support is the C-terminal immobilization of a fully protected vancomycin
to a proallyl selenium-resin.
107
After deglycosylation and semisynthetic reglycosy-
lation, the glycopeptide was cleaved by H
2
O
2
-mediated oxidation from the
resin under simultanous conversion to the allyl ester. With this approach, several
variously monoglycosylated and/or AA1-altered glycopeptides have been
synthesized and evaluated for their antibiotic activity.
108
Wong et al. reported on
the glycosylation of a protected vancomycin with non-natural disaccharides and
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