Structural and conformational studies of the heparan sulfate mimetic PI-88

Abstract

The heparan sulfate mimetic PI-88 is a complex mixture of sulfated oligosaccharides with anti-metastatic and anti-angiogenic activity due to its potent inhibition of heparanase and heparan sulfate-dependent angiogenic growth factors. It was recently in Phase III clinical trials for postresection hepatocellular carcinoma. The major oligosaccharide constituents of PI-88 were prepared for the first time by sulfonation of individually purified phosphorylated oligosaccharides isolated from the PI-88 precursor. PI-88 and its components were subjected to detailed 1D and 2D NMR spectroscopic analysis. The spectra of the individual components greatly assisted the assignment of minor resonances in the 1H NMR spectrum of PI-88. The data also showed that the majority of the oligosaccharides in PI-88 are fully sulfated and that undersulfated species present are largely due to anomeric desulfation. The solution conformation of the phosphomannopentaose sulfate (major component) of PI-88 was then determined by a combination of molecular dynamics simulations and NOE measurements which may provide insights into its binding interactions with target proteins.

Development of Improved Synthetic Routes to Pixatimod (PG545), a Sulfated Oligosaccharide-Steroid Conjugate

“…Full sulfation of the products was confirmed by analysis of the 1 H and HSQC NMR spectra, which showed clean anomeric doublets in the former, and all carbohydrate signals/cross-peaks shifted downfield relative to the polyol starting material . The spectra for PG545 were identical to those reported in the literature .…”

“…Full sulfation of the products was confirmed by analysis of the 1 H and HSQC NMR spectra, which showed clean anomeric doublets in the former, and all carbohydrate signals/cross-peaks shifted downfield relative to the polyol starting material. 29 The spectra for PG545 were identical to those reported in the literature. 1 Attempts were made to obtain low-and high-resolution mass spectroscopy data using various electrospray ionization techniques and instruments, but the results obtained were not satisfactory.…”

Curcumin inhibits CT26 cells metastasis by decreasing heparanase expression

“…HPSE inhibitors, including heparin and its analogs, sulfated oligosaccharides and their analogs, Abs, natural drugs, and RNA interference, have been used in research and clinical treatment of malignancies, 13 and the sulfated oligosaccharide PI-88 is under the clinical phase III experiment. 14,15 PG545, an HS-mimetic HSPE inhibitor, elicits lymphoma cell apoptosis. 16 Although these HPSE inhibitors have significant anticancer activities, they still have some disadvantages, such as heparin affects the coagulation system, sulfated oligosaccharides inhibit HPSE extensively, and HPSE Abs are too expensive.…”

“…HPSE inhibitors, including heparin and its analogs, sulfated oligosaccharides and their analogs, Abs, natural drugs, and RNA interference, have been used in research and clinical treatment of malignancies, 13 and the sulfated oligosaccharide PI‐88 is under the clinical phase III experiment 14,15 . PG545, an HS‐mimetic HSPE inhibitor, elicits lymphoma cell apoptosis 16 …”