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Targeting Glycosaminoglycans with Small Molecules : Design, Synthesis, and Applications

  • Author(s): Weiss, Ryan Joseph
  • et al.
Abstract

Glycosaminoglycans (GAGs) are a family of long anionic polysaccharides that are found on the surface of all cells and in the extracellular matrix. These complex cell surface carbohydrates are known to regulate important biological processes and have been implicated in certain pathophysiological states. Thus, interest exists in agents controlling GAG--protein interactions as both therapeutics and glycobiology tools. The accessibility and versatility of small molecules that can antagonize GAG--protein interactions make them particularly attractive as drug candidates. This motivated the work shown here, which addressed the design and preparation of small molecules for targeting and detecting GAGs. Surfen, bis-2-methyl-4- amino-quinolyl-6-carbamide, was previously reported as a small molecule antagonist of heparan sulfate (HS), a key cell surface GAG. To generate structure-activity relationships, a series of rationally designed surfen analogs was synthesized, where its dimeric structure, exocyclic amines, and urea linker region were modified to probe the role of each moiety in recognizing HS. An in vitro assay monitoring inhibition of fibroblast growth factor 2 binding to wild-type CHO cells was utilized to quantify interactions with cell surface HS. The dimeric molecular structure of surfen and its aminoquinoline ring systems were essential for its interaction with HS, and certain dimeric analogs displayed higher inhibitory potency than surfen. These molecules were also able to antagonize other HS--protein interactions including the binding of soluble RAGE to HS. Importantly, selected analogs were shown to neutralize heparin and other heparinoids, including the synthetic pentasaccharide fondaparinux, for which no antidote exists, both in vitro and in vivo in mice. Additional studies were also performed to highlight other potential applications for surfen and its analogs. Heparin, the most highly sulfated GAG, is used as an anticoagulant in surgery and for the treatment of certain thrombotic diseases. Adverse side effects can occur with heparin administration; therefore, it is necessary to closely monitor heparin plasma levels in patients. Here, we utilize surfen as a selective turn- on fluorescent probe for the detection of heparin in human plasma samples. A detailed photophysical analysis helped to further elucidate this molecule's unique interaction with heparin and the nature of its turn-on fluorescence features. Surfen demonstrates aggregation-induced emission upon forming a supramolecular complex with heparin in solution and exhibits photophysical sensitivity to its microenvironment

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