Chemistry Reference
In-Depth Information
as they are implicated in many biological processes and their regulation.
They can be inhibitors of enzymes which require generally well defined
structures and conformations, they can make complexes with proteins to
activate or inactivate them. The diculty to synthesize or to produce well
defined oligosaccharides has set many questions about the fine struc-
ture, the charge localisation and density, the length and conformation of
oligosaccharides. Is it possible to readily produce oligosaccharides that
keep the expected biological activities for pharmaceutical and other ap-
plications? The literature covered in this chapter treats on the impact of
anionic oligosaccharides on various biological aspects such as antico-
agulation, cell proliferation, cells and viruses interactions, Alzheimer
disease and plant protection over the period 2008-present. It does not
include patents and anionic oligosaccharides largely modified like gly-
coconjugates or oligosaccharides for epitope determination,
lectine
binding or surface plasmon resonance imaging.
4.1 Blood coagulation cascade
A well-defined pentasaccharide found in the structure of heparin is
known to disrupt the blood coagulation cascade by inactivation of pro-
teases such as thrombin or factor Xa. This pentasaccharide leads to a
change of conformation of antithrombin which interacts more rapidly
with thrombin (for oligosaccharides with DP W 5) or factor Xa. Work is
done to make variations around this pentasaccharide to ameliorate the
biological activities.
101
Guerrini et al.
102
studied the effects of both
structural and sulphation changes made on octasaccharide analogues.
They have identified a critical 3-O-sulphated glucosamine for anti-
thrombin anity and showed that the octasaccharides should give
additional contacts with antithrombin facilitating the complex formation
compared to the pentasaccharide. Torri et al.
103
studied also the anti-
thrombin anity of oligosaccharides from low molecular weight
heparins depending on their composition with the aim of establishing
correlations between structural features and their antithrombin medi-
ated anticoagulant activity. Liu et al. prepared a HS nonasaccharide with
an antithrombin binding anity of 3 nM while a heptasaccharide did not
display comparable values.
104
Borb´s et al. synthesized bioisosteric
sulfonic acid analogues of the antithrombin binding pentasaccharide
domain of heparin with good factor Xa inhibition. They showed that the
ecacy of inhibition was depending of the number of sulfonate groups
with a decrease of inhibition from two sulfonate groups to three probably
as a result of a conformational change.
105
Petitou et al.
106
described a
modified pentasaccharide linked to a direct thrombin inhibitor which
can be neutralised by the injection of a specific antidote.
4.2 Cell proliferation
Anionic oligosaccharides play important roles in cell proliferation and
cancer biology, including angiogenesis, metastasis and tumour pro-
gression. Various oligosaccharide derivatives are able to act as anti-
cancer agents. PI-88 (a highly sulphated phosphomannopentaose in
mixture with DP 2 to 6 oligomers)
is known as an angiogenesis
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