Surfen, a small molecule antagonist of heparan sulfate

Abstract

In a search for small molecule antagonists of heparan sulfate, we examined the activity of bis-2-methyl-4-amino-quinolyl-6-carbamide, also known as surfen. Fluorescence-based titrations indicated that surfen bound to glycosaminoglycans, and the extent of binding increased according to charge density in the order heparin > dermatan sulfate > heparan sulfate > chondroitin sulfate. All charged groups in heparin (N-sulfates, O-sulfates, and carboxyl groups) contributed to binding, consistent with the idea that surfen interacted electrostatically. Surfen neutralized the anticoagulant activity of both unfractionated and low molecular weight heparins and inhibited enzymatic sulfation and degradation reactions in vitro. Addition of surfen to cultured cells blocked FGF2-binding and signaling that depended on cell surface heparan sulfate and prevented both FGF2-and VEGF 165-mediated sprouting of endothelial cells in Matrigel. Surfen also blocked heparan sulfate-mediated cell adhesion to the Hep-II domain of fibronectin and prevented infection by HSV-1 that depended on glycoprotein D interaction with heparan sulfate. These findings demonstrate the feasibility of identifying small molecule antagonists of heparan sulfate and raise the possibility of developing pharmacological agents to treat disorders that involve glycosaminoglycan-protein interactions.antithrombin ͉ glycosaminoglycans ͉ growth factors ͉ viral infection ͉ angiogenesis

Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia

“…This compound binds more strongly to cellular HS than CS. 30 Surfen, like PF4, interacts with HS through electrostatic interactions. Addition of surfen to cultured Chinese hamster ovary cells blocks fibroblast growth factor 2 binding and signaling that depends on cell surface HS.…”

“…Surfen (bis-2-methyl-4-aminoquinolyl-6-carbamide) has been shown to block hPF4 binding to surface GAGs. 30 Originally synthesized by the Open Chemical Repository in the Developmental Therapeutic Program at the National Cancer Institute (NSC12155), surfen was kindly provided by Dr Jeffrey Esko (Glycobiology Research and Training Center, La Jolla, CA). A stock solution of surfen (30mM) was prepared in dimethyl sulfoxide (DMSO) and stored in glass containers under nitrogen at Ϫ80°C in the absence of light.…”

Cyclic tensile strain triggers a sequence of autocrine and paracrine signaling to regulate angiogenic sprouting in human vascular cells

“…Vascular cells were cultured in 2D directly on elastomeric poly(dimethylsiloxane) (PDMS) substrates and in fibrin 3D cultures. In vitro sprouting was used as a model for the initial stages of angiogenesis, as previously described (25)(26)(27)(28). Vascular cell cultures were exposed to cyclic tensile strain with an amplitude of 7%, representative of that experienced by vascular cells in large vessels, and also in the same range as previous calculations of capillary wall strain (29,30).…”

Inclusion excluded: Chiroptical sensing of the external surface of sulfated cyclodextrins

“…The protonated basic ring nitrogens (pK a 9.17 [14]) may be involved in electrostatic interactions while the -NH 2 substituents act as H-donors. Noticeably, the replacement of the -NH 2 groups with -H, -OH or -OMe substituents completely abolishes the heparan sulfate binding of surfen [15,16]. In addition, electrostatic complexes of basic organic compounds formed with sulfated glycosaminoglycans are highly sensitive to the ionic strength of the solution and dissociate at physiological salt concentration [17,18].…”

“…Surfen is a bis-aminoquinoline derivative (Scheme 1) that can bind to proteins [6,7] as well as anionic, linear-chain polysaccharides (e.g., heparin, chondroitin sulfate, dermatan sulfate) modulating a number of functional glycosaminoglycan-protein interactions [8][9][10]. …”