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Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth

A series of polysulfated penta- and tetrasaccharide glycosides containing α(1→3)/α(1→2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2, and VEGF)...

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Main Authors: Johnstone, Ken D. (Author) , Karoli, Tomislav (Author) , Liu, Ligong (Author) , Dredge, Keith (Author) , Copeman, Elizabeth (Author) , Li, Cai Ping (Author) , Davis, Kat (Author) , Hammond, Edward (Author) , Bytheway, Ian (Author) , Kostewicz, Edmund (Author) , Chiu, Francis C. K. (Author) , Shackleford, David M. (Author) , Charman, Susan A. (Author) , Charman, William N. (Author) , Harenberg, Job (Author) , Gonda, Thomas J. (Author) , Ferro, Vito (Author)
Format: Article (Journal)
Language:English
Published: 25 February 2010
In: Journal of medicinal chemistry
Year: 2010, Volume: 53, Issue: 4, Pages: 1686-1699
ISSN:1520-4804
DOI:10.1021/jm901449m
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/jm901449m
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Author Notes:Ken D. Johnstone, Tomislav Karoli, Ligong Liu, Keith Dredge, Elizabeth Copeman, Cai Ping Li, Kat Davis, Edward Hammond, Ian Bytheway, Edmund Kostewicz, Francis C. K. Chiu, David M. Shackleford, Susan A. Charman, William N. Charman, Job Harenberg, Thomas J. Gonda, and Vito Ferro
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Summary:A series of polysulfated penta- and tetrasaccharide glycosides containing α(1→3)/α(1→2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2, and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.
Item Description:Published online 3 February 2010
Gesehen am 28.08.2023
Physical Description:Online Resource
ISSN:1520-4804
DOI:10.1021/jm901449m

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