Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth.
A series of polysulfated penta- and tetrasaccharide glycosides containing alpha(1-->3)/alpha(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.
Drug Design Group, Progen Pharmaceuticals Limited, Toowong, Queensland 4066, Australia.
Ken D
KD
Johnstone
Tomislav
T
Karoli
Ligong
L
Liu
Keith
K
Dredge
Elizabeth
E
Copeman
Cai Ping
CP
Li
Kat
K
Davis
Edward
E
Hammond
Ian
I
Bytheway
Edmund
E
Kostewicz
Francis C K
FC
Chiu
David M
DM
Shackleford
Susan A
SA
Charman
William N
WN
Charman
Job
J
Harenberg
Thomas J
TJ
Gonda
Vito
V
Ferro
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D006027:Glycosides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006497:Heparan Sulfate / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099175:Heparanase
D020533:Angiogenesis Inhibitors; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D006027:Glycosides; D006497:Heparan Sulfate; D009844:Oligosaccharides; D013463:Sulfuric Acid Esters; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase