Synthesis, radiolabeling with fluorine-18 and preliminary in vivo evaluation of a heparan sulphate mimetic as potent angiogenesis and heparanase inhibitor for cancer applications

Kühnast, Bertrand; Hadri, Ahmed El; Boisgard, Raphaël; Hinnen, Françoise; Richard, S.; Caravano, Audrey; Nancy-Portebois, Vanessa; Petitou, Maurice; Tavitian, Bertrand; Dollé, Frédéric

doi:10.1039/c5ob02513c

Cited by 18 publications

(11 citation statements)

References 29 publications

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“…Dollé and coworkers synthesized an octasaccharide heparin mimetic that interfered with the process of angiogenesis and metastasis [102]. It potently inhibited heparanase, FGF2, VEGF, SDF-1α, PDGF-β, and cell proliferation in vitro and is being tested in vivo in animal models.…”

Section: Gag Mimeticsmentioning

confidence: 99%

Glycosaminoglycans and Glycosaminoglycan Mimetics in Cancer and Inflammation

Morla

2019

IJMS

173

125

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Glycosaminoglycans (GAGs) are a class of biomolecules expressed virtually on all mammalian cells and usually covalently attached to proteins, forming proteoglycans. They are present not only on the cell surface, but also in the intracellular milieu and extracellular matrix. GAGs interact with multiple ligands, both soluble and insoluble, and modulate an important role in various physiological and pathological processes including cancer, bacterial and viral infections, inflammation, Alzheimer’s disease, and many more. Considering their involvement in multiple diseases, their use in the development of drugs has been of significant interest in both academia and industry. Many GAG-based drugs are being developed with encouraging results in animal models and clinical trials, showcasing their potential for development as therapeutics. In this review, the role GAGs play in both the development and inhibition of cancer and inflammation is presented. Further, advancements in the development of GAGs and their mimetics as anti-cancer and anti-inflammatory agents are discussed.

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Section: Gag Mimeticsmentioning

confidence: 99%

Glycosaminoglycans and Glycosaminoglycan Mimetics in Cancer and Inflammation

Morla

2019

IJMS

173

125

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“…Karoli et al demonstrated that carbohydrate-based HS-mimicking compounds, PI-88 and analogues, inhibit heparanase and compete with growth factors (FGF-1, FGF-2, and VEGF) for binding to HS, and therefore impact anti-angiogenic and anti-metastatic activity [48,181]. Another octasaccharide-based heparin mimetic synthesized by Dollé and coworkers was characterized in vitro for its binding affinities and towards VEGF-A, FGF-2, PDGF-β, and SDF1-α using the BIAcore technology and for the potential inhibition in an heparanase activity assay [182]. This novel molecule could thus potentially inhibit angiogenesis by interfering with components of the extracellular matrix.…”

Section: Targeting the Tumor Microenvironmentmentioning

confidence: 99%

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

2020

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This review comes as a part of the special issue “Emerging frontiers in GAGs and mimetics”. Our interest is in the manipulation of heparan sulfate (HS) turnover by employing HS mimetics/heparin derivatives that exert pleiotropic effects and are interesting for interfering at multiple levels with pathways in which HS is implicated. Due to the important role of heparanase in HS post-biosynthetic modification and catabolism, we focus on the possibility to target heparanase, at both extracellular and intracellular levels, a strategy that can be applied to many conditions, from inflammation to cancer and neurodegeneration.

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“…Kuhnast et al [ 241 ] reported the in vitro antiangiogenic properties of a rationally designed octasaccharide-based HS mimetic and of its fluoropyridinilated radioactive derivative. The parental oligosaccharide showed strong affinity for VEGF-A, FGF2, PDGF-β, and SDF-1α, as well as potent heparanase inhibitory activity.…”

Section: New Molecules and Perspectivesmentioning

confidence: 99%

Heparan Sulfate Mimetics in Cancer Therapy: The Challenge to Define Structural Determinants and the Relevance of Targets for Optimal Activity

Lanzi

Cassinelli

2018

Molecules

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Beyond anticoagulation, the therapeutic potential of heparin derivatives and heparan sulfate (HS) mimetics (functionally defined HS mimetics) in oncology is related to their ability to bind and modulate the function of a vast array of HS-binding proteins with pivotal roles in cancer growth and progression. The definition of structural/functional determinants and the introduction of chemical modifications enabled heparin derivatives to be identified with greatly reduced or absent anticoagulant activity, but conserved/enhanced anticancer activity. These studies paved the way for the disclosure of structural requirements for the inhibitory effects of HS mimetics on heparanase, selectins, and growth factor receptor signaling, as well as for the limitation of side effects. Actually, HS mimetics affect the tumor biological behavior via a multi-target mechanism of action based on their effects on tumor cells and various components of the tumor microenvironment. Emerging evidence indicates that immunomodulation can participate in the antitumor activity of these agents. Significant ability to enhance the antitumor effects of combination treatments with standard therapies was shown in several tumor models. While the first HS mimetics are undergoing early clinical evaluation, an improved understanding of the molecular contexts favoring the antitumor action in certain malignancies or subgroups is needed to fully exploit their potential.

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Synthesis, radiolabeling with fluorine-18 and preliminary in vivo evaluation of a heparan sulphate mimetic as potent angiogenesis and heparanase inhibitor for cancer applications

Cited by 18 publications

References 29 publications

Glycosaminoglycans and Glycosaminoglycan Mimetics in Cancer and Inflammation

Glycosaminoglycans and Glycosaminoglycan Mimetics in Cancer and Inflammation

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

Heparan Sulfate Mimetics in Cancer Therapy: The Challenge to Define Structural Determinants and the Relevance of Targets for Optimal Activity

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