Antiangiogenic heparin-derived heparan sulfate mimics
B. Casu and A. Naggi
G.Ronzoni Institute for Chemical and Biochemical Research,
Milan, Italy
Abstract: Heparan sulfate (HS) is a glycosaminoglycan (GAG)
widely distributed as a proteoglycan on the cell surface and in the
extracellular matrix of animal tissues. Among other important physiological
functions, its polysaccharide chains mediate cell proliferation by binding
growth factors [fibroblast growth factor (FGF), vascular endothelial
growth factor (VEGF)], which are released in active form through the
action of the enzyme heparanase
overexpressed by tumor cells. HS is constituted of alternating disaccharide
sequences of variously sulfated uronic acid (D-glucuronic,
GlcA, or L-iduronic, IdoA) and glucosamine (N-acetylated,
GlcNAc, or N-sulfated, GlcNSO3). HS mimics can be
obtained by chemical modification of heparin, a more highly sulfated
GAG clinically used as an anticoagulant and antithrombotic drug. With
the aim of obtaining antagonists of FGFs as potential inhibitors of
tumor neo-vascularization (angiogenesis), arrays of short FGF-binding
sequences have been obtained by generating sulfation gaps within the
prevalent (IdoA2SO3GlcNSO36SO3)n
sequences of heparin, by controlled base-catalyzed removal of 2-O-sulfate
groups of IdoA2SO3 residues.The C(2)C(3) bond of all
nonsulfated uronic acid residues have then been split with periodate,
to generate flexible joints along the polysaccharide chain. The novel
heparin derivative (poly-PST.sU), chiefly made up of the repeating tetrasaccharide
units GlcNSO36SO3 IdoA2SO3 GlcNSO36SO3 sU
(where sU is a glycol-split and reduced
uronic acid residue) binds FGF2 as strongly as heparin. However, it
is a poor inducer of formation of FGF2 dimers and of complexes with
FGF receptors, required for triggering mitogenic signals. NMR and molecular
modeling studies indicate that formation of these higher-
order complexes is prevented by the unfavorable conformation induced
by glycol-split residues. In a parallel study, partially N-acetylated
heparins have been obtained that efficiently
inhibit heparanase upon glycol-splitting. It is noteworthy that glycol-splitting
involves inactivation of the active site for antithrombin, with consequent
loss of anticoagulant activity. In contrast, poly-PST.sU and some of
its analogs show potent antiangiogenic activity in in vivo
models in which heparin is either proangiogenic or inactive.
*Pure Appl.Chem. 75,
141-419 (2003). An issue of reviews and research papers based on
lectures presented at the 23rd IUPAC International Symposium on the
Chemistry of Natural Products, Florence, Italy, 28 July - 2 August 2002.
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