Synthesis and Biological Evaluation of a Heparin‐Like Hexasaccharide with the Structural Motifs for Binding to FGF and FGFR

Paz, José L. de; Martín‐Lomas, Manuel

doi:10.1002/ejoc.200400799

Cited by 46 publications

(24 citation statements)

References 36 publications

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“…18 We have found that the structure of the hexasaccharide 1 has the same overall features as the previously studied heparin-like oligosaccharides, a rigid linear structure due to the geometry of the glycosidic linkages driven by the electrostatic repulsions between the charges of the sulphate groups. [14][15][16][17] In particular, it is very close to the structure of 2 that has remarkable mitogenic activity mediated by FGF-1 and shares many of its structural characteristics with the nonsymmetrical distribution of the sulphate groups on both sides of the molecule.…”

Section: Discussionsupporting

confidence: 64%

“…1). [14][15][16][17][18] The heparin regular region is made of repetitions of the D-GlcN-L-IdoA disaccharide, connected by α(1-4) linkages, with sulphate groups at positions 6 and 2 of glucosamine, and 2 of iduronate. In previous reports from our group, we have studied the activation of the mitogenic activity mediated by FGF-1 analysing the three-dimensional structure and dynamics of several hexa-and octasaccharides differing in their substitution pattern.…”

Section: Introductionmentioning

confidence: 99%

“…In previous reports from our group, we have studied the activation of the mitogenic activity mediated by FGF-1 analysing the three-dimensional structure and dynamics of several hexa-and octasaccharides differing in their substitution pattern. [14][15][16][17][18] The structure evaluation by high resolution NMR afforded similar overall shapes for the five substitution patterns: (a) two with sulphate groups on one side (1 18 and 2 15 ), (b) one similar to the regular heparin pattern with sulphates on both sides (3) 14 and (c) the other two with the absence of a type of sulphate group (either at position 6 primary hydroxyl of glucosamine residues, D-GlcN,6OH (4), 16 or at position 2 of the iduronate rings, L-Ido2OH (5)). 16 The activity results disclosed a strong influence of the sulphation pattern; while the regular heparin pattern (3) showed reasonable activity, the axially asymmetric substitution (2) had an improved activity (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…19 However, the biological results were negative in terms of activity. 18 Note that in compound 1 the spatial orientation of the negative charges is similar to 2, with five sulfate groups displayed on one side of the helical structure. However, compound 1 contains the alternative sequence of constituent monosaccharides with an L-iduronic acid unit at the non-reducing end and a D-glucosamine residue at the reducing terminal.…”

mentioning

confidence: 96%

“…This is reflected in the values of the intra-ring three-bond coupling constants and in the H2-H5 distance, that in some cases give observable NOE peaks. 4,18 We have performed several analyses of the populations of conformers of the L-IdoA residues assuming a mixture of two conformations, 1 C 4 and 2 S 0 , in fast equilibrium in the chemical shift time scale (Table 3). Interestingly the iduronate rings of 1 have a rich and varied behaviour.…”

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confidence: 99%

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3D structure of a heparin mimetic analogue of a FGF-1 activator. A NMR and molecular modelling study

et al. 2013

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The motional behaviour of heparin oligosaccharides in solution is best described as a top rotor having two perpendicular rotation axes. This prevents an accurate extraction of interprotonic distances by NOESY/ROESY based methods. In this paper, we describe the solution structure of the hexasaccharide 1 calculated from high exactitude distance data obtained from off-resonance ROESY combined with a long MD simulation of 500 ns. In previous studies, we have found that two synthetic hexasaccharides having the sulphate groups directed towards one side of its central plane have an opposite biological activity, while 1 is unable to activate the FGF-1 signalling pathway, the other (2) is even more active than the regular region derived hexasaccharide (3) that mimics the natural active compound, heparin. From the structural analysis it was concluded that 1 has similar three-dimensional characteristics to 2 or 3 and therefore the differences in the activity should be due to the arrangement of the sulphate groups within the hexasaccharidic sequence.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 96%

mentioning

confidence: 99%

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3D structure of a heparin mimetic analogue of a FGF-1 activator. A NMR and molecular modelling study

et al. 2013

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Chitosan‐Based Heparan Sulfate Mimetics Promote Epidermal Formation in a Human Organotypic Skin Model

Farrugia

Kim

et al. 2018

Adv Funct Materials

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Biomimetic materials that replicate biological functions have great promise for use as therapeutics in regenerative medicine applications. Heparan sulfate (HS) is the natural binding partner for growth factors enabling longer half-lives and potentiation of their signaling. In this study a water soluble chitosan-arginine is modified with sulfate moieties in order to mimic the structure of HS. Sulfated chitosan-arginine with a degree of sulfation of 58% binds fibroblast growth factor 2 with higher affinity than HS. The sulfated chitosanarginine also promotes epithelial cell migration and supports the formation of an expanded epidermis in an organotypic skin model. Furthermore, sulfated chitosan-arginine promotes the expression of the HS proteoglycan, perlecan, by both epithelial and fibroblast cells. Perlecan itself modulates the activity of mitogens and is essential for the formation of the epidermis. The synthesized sulfated Ch-Arg derivatives mimic HS, support formation of the epidermis, and thus have the potential to assist in wound healing.

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Chemical Synthesis of Syndecan‐3 Glycopeptides Bearing Two Heparan Sulfate Glycan Chains

Yoshida

Yang

et al. 2014

Angewandte Chemie

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Despite the ubiquitous presence of proteoglycans in mammalian systems, methodologies to synthesize this class of glycopeptides with homogeneous glycans are not well developed. Herein, we report the first synthesis of a glycosaminoglycan family glycopeptide containing two different heparan sulfate chains, namely the extracellular domain of syndecan‐3. With the large size and tremendous structural complexity of these molecules, multiple unexpected obstacles were encountered during the synthesis, including high sensitivity to base treatment and the instability of glycopeptides with two glycan chains towards catalytic hydrogenation conditions. A successful strategy was established by constructing the partially deprotected single glycan chain containing glycopeptides first, followed by union of the glycan‐bearing fragments and cleavage of the ester‐type protecting groups. This work lays the foundation for preparing other members of this important class of molecules.

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Synthesis and Biological Evaluation of a Heparin‐Like Hexasaccharide with the Structural Motifs for Binding to FGF and FGFR

Cited by 46 publications

References 36 publications

3D structure of a heparin mimetic analogue of a FGF-1 activator. A NMR and molecular modelling study

3D structure of a heparin mimetic analogue of a FGF-1 activator. A NMR and molecular modelling study

Chitosan‐Based Heparan Sulfate Mimetics Promote Epidermal Formation in a Human Organotypic Skin Model

Chemical Synthesis of Syndecan‐3 Glycopeptides Bearing Two Heparan Sulfate Glycan Chains

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