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.
Johnstone
Ken D
KD
Drug Design Group, Progen Pharmaceuticals Limited, Toowong, Queensland 4066, Australia.
Karoli
Tomislav
T
Liu
Ligong
L
Dredge
Keith
K
Copeman
Elizabeth
E
Li
Cai Ping
CP
Davis
Kat
K
Hammond
Edward
E
Bytheway
Ian
I
Kostewicz
Edmund
E
Chiu
Francis C K
FC
Shackleford
David M
DM
Charman
Susan A
SA
Charman
William N
WN
Harenberg
Job
J
Gonda
Thomas J
TJ
Ferro
Vito
V
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