Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88).
The phosphosulfomannan 1 (PI-88) is a mixture of highly sulfated oligosaccharides that is currently undergoing clinical evaluation in cancer patients. As well as its anticancer properties, 1 displays a number of other interesting biological activities. A series of analogues of 1 were synthesized with a single carbon (pentasaccharide) backbone to facilitate structural characterization and interpretation of biological results. In a fashion similar to 1, all compounds were able to inhibit heparanase and to bind tightly to the proangiogenic growth factors FGF-1, FGF-2, and VEGF. The compounds also inhibited the infection of cells and cell-to-cell spread of herpes simplex virus (HSV-1). Preliminary pharmacokinetic data indicated that the compounds displayed different pharmacokinetic behavior compared with 1. Of particular note was the n-octyl derivative, which was cleared 3 times less rapidly than 1 and may provide increased systemic exposure.
Karoli
Tomislav
T
Drug Design Group, Progen Industries Limited, Brisbane, Queensland, Australia.
Liu
Ligong
L
Fairweather
Jon K
JK
Hammond
Edward
E
Li
Cai Ping
CP
Cochran
Siska
S
Bergefall
Kicki
K
Trybala
Edward
E
Addison
Russell S
RS
Ferro
Vito
V
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D008297:Male; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020349:Surface Plasmon Resonance; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry; D000099175:Heparanase
D020533:Angiogenesis Inhibitors; D000998:Antiviral Agents; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D009844:Oligosaccharides; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C120158:phosphomannopentaose sulfate