Undersulfated and Glycol-Split Heparins Endowed with Antiangiogenic Activity

Benito Casu, Marco Guerrini, Sara Guglieri, Annamaria Naggi, Marta Perez, Giangiacomo Torri, Giuseppe Cassinelli, Domenico Ribatti, Paolo Carminati, Giuseppe Giannini, Sergio Penco, Claudio Pisano, Mirella Belleri, Marco Rusnati, Marco Presta

Research output: Contribution to journalArticlepeer-review


Tumor neovascularization (angiogenesis) is regarded as a promising target for anticancer drugs. Heparin binds to fibroblast growth factor-2 (FGF2) and promotes the formation of ternary complexes with endothelial cell surface receptors, inducing an angiogenic response. As a novel strategy to generate antiangiogenic substances exploiting binding to FGF2 while preventing FGF receptor (FGFR) activation, sulfation gaps were generated along the heparin chains by controlled alkali-catalyzed removal of sulfate groups of iduronic acid 2-O-sulfate residues, giving rise to the corresponding epoxide derivatives. A new class of heparin derivatives was then obtained by opening the epoxide rings followed by oxidative glycol-splitting of the newly formed (and the preexisting) nonsulfated uronic acid residues. In vitro these heparin derivatives prevent the formation of FGFR/FGF2/heparan sulfate proteoglycan ternary complexes and inhibit FGF2-stimulated endothelial cell proliferation. They exert an antiangiogenic activity in the chick embryo chorioallantoic membrane assay, where the parent heparin is inactive. Low and very low molecular weight derivatives of a prototype compound, as well as its glycine and taurine derivatives obtained by reductive amination of glycol-split residues, retained the angiostatic activity. A significant relationship was found between the extent of glycol-splitting and the FGF2-antagonist/ angiostatic activities of these heparin derivatives. Molecular dynamics calculations support the assumption that glycol-split residues act as flexible joints that, while favoring 1:1 binding to FGF2, disrupt the linearity of heparin chains necessary for formation of active complexes with FGFRs.

Original languageEnglish
Pages (from-to)838-848
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number4
Publication statusPublished - Feb 12 2004

ASJC Scopus subject areas

  • Organic Chemistry

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