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

Autor: Spijkers-Shaw S; Ferrier Research Institute, Victoria University of Wellington, 6140, Wellington, New Zealand., Campbell K; Department of Pathology, Dunedin School of Medicine, University of Otago, 9054, Dunedin, New Zealand., Shields NJ; Department of Pathology, Dunedin School of Medicine, University of Otago, 9054, Dunedin, New Zealand.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, 2006, Sydney, Australia., Miller JH; School of Biological Sciences, Victoria University of Wellington, Kelburn, 6140, Wellington, New Zealand., Rendle PM; Ferrier Research Institute, Victoria University of Wellington, 6140, Wellington, New Zealand., Jiao W; Ferrier Research Institute, Victoria University of Wellington, 6140, Wellington, New Zealand., Young SL; Department of Pathology, Dunedin School of Medicine, University of Otago, 9054, Dunedin, New Zealand.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, 2006, Sydney, Australia., Zubkova OV; Ferrier Research Institute, Victoria University of Wellington, 6140, Wellington, New Zealand.
Jazyk: angličtina
Zdroj: Chemistry, an Asian journal [Chem Asian J] 2022 Jun 15; Vol. 17 (12), pp. e202200228. Date of Electronic Publication: 2022 Apr 29.
DOI: 10.1002/asia.202200228
Abstrakt: 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.
(© 2022 The Authors. Chemistry - An Asian Journal published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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