Synthesis of Novel Glycolipid Mimetics of Heparan Sulfate and Their Application in Colorectal Cancer Treatment in a Mouse Model

Abstract

Heparan sulfate (HS) is a highly sulfated natural carbohydrate that plays crucial roles in cancer, inflammation, and angiogenesis. Heparanase (HPSE) is the sole HS degrading endoglycosidase that cleaves HS at structure‐dependent sites along the polysaccharide chain. Overexpression of HPSE by cancer cells correlates with increased tumor size and enhanced metastasis. Previously we have shown that a tetramer HS mimetic is a potent HPSE inhibitor displaying remarkable anticancer activity in vivo. Building on that work, we report the synthesis and testing of a novel library of single entity trimer glycolipid mimetics that effectively inhibit HPSE at low nanomolar concentrations. A lipophilic arm was introduced to assess whether an improvement of pharmacokinetics and plasma residence time would offset the reduction in charge and multivalency. Preclinical tests in a mouse syngeneic model showed effective tumor growth inhibition by the tetramer but not the trimer glycomimetic.

Synthesis and Detection of BODIPY‐, Biotin‐, and 19F‐ Labeled Single‐Entity Dendritic Heparan Sulfate Mimetics

“…However, a structural redesign was necessary because Tet-29 is devoid of a synthetic handle, and trimeric derivatives did not display anti-cancer efficacy. [32] This led us to the structure represented by Scheme 1. Synthesis of labeled derivatives starting from diethyl 3-oxopentanedioate (6).…”

Synthesis and Detection of BODIPY‐, Biotin‐, and 19F‐ Labeled Single‐Entity Dendritic Heparan Sulfate Mimetics

“…However, a structural redesign was necessary because Tet-29 is devoid of a synthetic handle, and trimeric derivatives did not display anti-cancer efficacy. [32] This led us to the structure represented by Scheme 1. Synthesis of labeled derivatives starting from diethyl 3-oxopentanedioate (6).…”

“…The authors have cited additional references within the Supporting Information. [32,35,36,47] Centenary Institute and the University of Sydney, for assistance with flow cytometry and live cell imaging, and acknowledge Laboratory Animal Services at the University of Sydney for providing animal husbandry and assistance. The graphical abstract and schematic diagram in Figure 2 (Figure 2A) were made using Biorender.com.…”

“…[31] Previously, by utilizing single-entity dendritic scaffolds, we have reported three libraries of nontoxic and nonanticoagulant HS mimetics with biological effects in multiple sclerosis and cancer models. [32][33][34][35] Of the compounds developed, Tet-29 (4, Figure 1) was identified as the lead compound and, as such, we were interested in improving the understanding of the mechanisms of action by which the compound has biological activity. Herein, we report the redesign of Tet-29 to a pentameric structure with a synthetic anchor (5, Figure 1), enabling rapid preparation of various labeled derivatives from a common late-stage precursor whilst retaining comparable biological activity.…”

“…Previously, by utilizing single‐entity dendritic scaffolds, we have reported three libraries of nontoxic and non‐anticoagulant HS mimetics with biological effects in multiple sclerosis and cancer models [32–35] . Of the compounds developed, Tet‐29 ( 4 , Figure 1) was identified as the lead compound and, as such, we were interested in improving the understanding of the mechanisms of action by which the compound has biological activity.…”