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Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88).

Journal article
Authors Tomislav Karoli
Ligong Liu
Jon K Fairweather
Edward Hammond
Cai Ping Li
Siska Cochran
Kicki Bergefall
Edward Trybala
Russell S Addison
Vito Ferro
Published in Journal of medicinal chemistry
Volume 48
Issue 26
Pages 8229-36
ISSN 0022-2623
Publication year 2005
Published at Institute of Laboratory Medicine, Dept of Clinical Virology
Pages 8229-36
Language en
Links dx.doi.org/10.1021/jm050618p
Keywords Angiogenesis Inhibitors, chemical synthesis, pharmacokinetics, pharmacology, Animals, Antiviral Agents, pharmacology, Blood Platelets, enzymology, Cells, Cultured, Cercopithecus aethiops, Fibroblast Growth Factor 1, chemistry, Fibroblast Growth Factor 2, chemistry, Glucuronidase, antagonists & inhibitors, Herpesvirus 1, Human, drug effects, Humans, Male, Oligosaccharides, chemical synthesis, pharmacokinetics, pharmacology, Rats, Rats, Sprague-Dawley, Surface Plasmon Resonance, Vascular Endothelial Growth Factor A, chemistry
Subject categories Medical and Health Sciences

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.

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