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

Johnstone, Ken D., Karoli, Tomislav, Liu, Ligong, Dredge, Keith, Copeman, Elizabeth, Li, Cai Ping, Davis, Kat, Hammond, Edward, Bytheway, Ian, Kostewicz, Edmund, Chiu, Francis C. K., Shackleford, David M., Charman, Susan A., Charman, William N., Harenberg, Job, Gonda, Thomas J. and Ferro, Vito (2010) Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth. Journal of Medicinal Chemistry, 53 4: 1686-1699. doi:10.1021/jm901449m

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Author Johnstone, Ken D.
Karoli, Tomislav
Liu, Ligong
Dredge, Keith
Copeman, Elizabeth
Li, Cai Ping
Davis, Kat
Hammond, Edward
Bytheway, Ian
Kostewicz, Edmund
Chiu, Francis C. K.
Shackleford, David M.
Charman, Susan A.
Charman, William N.
Harenberg, Job
Gonda, Thomas J.
Ferro, Vito
Title Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2010-02
Sub-type Article (original research)
DOI 10.1021/jm901449m
Open Access Status File (Author Post-print)
Volume 53
Issue 4
Start page 1686
End page 1699
Total pages 14
Place of publication Washington, DC, United States
Publisher The American Chemical Society
Collection year 2011
Language eng
Subject 03 Chemical Sciences
Formatted abstract
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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Sun, 07 Mar 2010, 00:03:10 EST