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

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