title: Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88).
abstract: 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.
authors.affiliation: Drug Design Group, Progen Industries Limited, Brisbane, Queensland, Australia.
authors.forename: Tomislav
authors.initials: T
authors.lastname: Karoli
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.forename: Jon K
authors.initials: JK
authors.lastname: Fairweather
authors.forename: Edward
authors.initials: E
authors.lastname: Hammond
authors.forename: Cai Ping
authors.initials: CP
authors.lastname: Li
authors.forename: Siska
authors.initials: S
authors.lastname: Cochran
authors.forename: Kicki
authors.initials: K
authors.lastname: Bergefall
authors.forename: Edward
authors.initials: E
authors.lastname: Trybala
authors.forename: Russell S
authors.initials: RS
authors.lastname: Addison
authors.forename: Vito
authors.initials: V
authors.lastname: Ferro
mesh_terms: 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
chemical_list: 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