Volume 89, Issue 2 pp. 215-222
Research Article

Studies on the structure of the complex of the boron neutron capture therapy drug, L-p-boronophenylalanine, with fructose and related carbohydrates: Chemical and 13C NMR evidence for the β-D-fructofuranose 2,3,6-(p-phenylalanylorthoboronate) structure

Brian K. Shull

Corresponding Author

Brian K. Shull

Glycosyn Pharmaceuticals, Inc., Cary, North Carolina 27513

Glycosyn Pharmaceuticals, Inc., Cary, North Carolina 27513Search for more papers by this author
David E. Spielvogel

David E. Spielvogel

New Concept Therapeutics, Inc., Cary, North Carolina 27513

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Gerald Head

Gerald Head

New Concept Therapeutics, Inc., Cary, North Carolina 27513

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Ramesh Gopalaswamy

Ramesh Gopalaswamy

Glycosyn Pharmaceuticals, Inc., Cary, North Carolina 27513

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Sabapathy Sankar

Sabapathy Sankar

Department of Chemistry, North Carolina State University, Raleigh, NC 27695

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Kevin Devito

Kevin Devito

Glycosyn Pharmaceuticals, Inc., Cary, North Carolina 27513

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Abstract

The complex of L-L-boronophenylalanine (L-p-BPA) with fructose has been used for the past 5 years in clinical trials of boron neutron capture therapy to treat both melanoma and glioblastoma multiforme. However, the structure of this complex in water buffered at physiologic pH has not been established. In the 1H NMR spectra (D2O buffered at pD 7.4) of the complex of L-p-BPA with various carbohydrates, the upfield chemical shifts of the aromatic protons of L-p-BPA confirm that the boron atom is negatively charged and tetrahedral. In the 13C NMR spectrum of the complex of L-p-BPA with U-13C labeled fructose, the chemical shifts and 1JCC coupling constants are consistent with fructose adopting the β-D-fructofuranose form. In addition, the 1JCC coupling constants along with the binding constants measured for L-p-BPA with a series of monosaccharides and disaccharides seem to suggest that the β-D-fructofuranose 2,3,6-(p-phenylalanylorthoboronate) structure strongly predominates, with free L-p-BPA and fructose the only other species detected. © 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 215–222, 2000

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