Undersulfated and glycol-split heparins endowed with antiangiogenic activity.
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.
Casu
Benito
B
G. Ronzoni Institute for Chemical and Biochemical Research, 20133 Milan, Italy. casu@ronzoni.it
Guerrini
Marco
M
Guglieri
Sara
S
Naggi
Annamaria
A
Perez
Marta
M
Torri
Giangiacomo
G
Cassinelli
Giuseppe
G
Ribatti
Domenico
D
Carminati
Paolo
P
Giannini
Giuseppe
G
Penco
Sergio
S
Pisano
Claudio
C
Belleri
Mirella
M
Rusnati
Marco
M
Presta
Marco
M
D000482:Allantois / Q000098:blood supply; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006018:Glycols / Q000737:chemistry*; D006493:Heparin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D011509:Proteoglycans / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry*; D014574:Uronic Acids / Q000737:chemistry
D020533:Angiogenesis Inhibitors; D006018:Glycols; D011509:Proteoglycans; D017468:Receptors, Fibroblast Growth Factor; D013451:Sulfonic Acids; D014574:Uronic Acids; D016222:Fibroblast Growth Factor 2; D006493:Heparin