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
“…Note that the main evidence of a pyranose B−N complex can be based on the pH profile of the binding constant together with the high 1 H coupling constants of, for example, H-3 and H-4 observed in D 2 O indicative of pyranose species. Species 3 in DMSO may take a tetrahedral anionic form, −B(OH) 3 - in aqueous solution (species 3‘) because nonionic trigonal-PhB(OH) 2 should be stabilized by OH - in aqueous solution, , as shown in the following equation. …”
Borates are known to interact with carbohydrate moieties expressed on the surface of biological membranes of a variety of cells, viruses, bacteria, and fungi. This study revealed the anomalous binding profile of borate in aqueous solution with N-acetylneuraminic acid (Neu5Ac, sialic acid) as a potential receptor site on the surfaces of biological membranes using (11)B, (1)H, (13)C, and (15)N nuclear magnetic resonance spectroscopies. 3-(Propionamido)phenylboronic acid (PAPBA) was chosen as the model borate compound. The equilibrium constant (K) for Neu5Ac binding to PAPBA was compared with those for glucose, mannose, and galactose, which are the major carbohydrate constituents of glycoproteins and glycolipids expressed on biological membranes. In the Neu5Ac/PAPBA system, the unusual pH dependency of the K values, a decrease in K with increasing pH, was observed, suggesting the formation of a trigonal-formed complex stabilized by the coordination of an amide group of Neu5Ac at the C-5 position to the boron atom, forming intramolecular B-N or B-O bonding. Furthermore, the anomalously high complexing ability at physiological pH 7.4 was confirmed for this system, with the K value 37.6 which is approximately 7 times higher than that for glucose. This exceptionally high value of K at physiological pH, compared to those of other sugars, strongly suggests that the boronic acid selectively recognizes the Neu5Ac residues of the glycosylated components including glycoproteins and gangliosides existing on the surface of the biological membranes.
“…Note that the main evidence of a pyranose B−N complex can be based on the pH profile of the binding constant together with the high 1 H coupling constants of, for example, H-3 and H-4 observed in D 2 O indicative of pyranose species. Species 3 in DMSO may take a tetrahedral anionic form, −B(OH) 3 - in aqueous solution (species 3‘) because nonionic trigonal-PhB(OH) 2 should be stabilized by OH - in aqueous solution, , as shown in the following equation. …”
Borates are known to interact with carbohydrate moieties expressed on the surface of biological membranes of a variety of cells, viruses, bacteria, and fungi. This study revealed the anomalous binding profile of borate in aqueous solution with N-acetylneuraminic acid (Neu5Ac, sialic acid) as a potential receptor site on the surfaces of biological membranes using (11)B, (1)H, (13)C, and (15)N nuclear magnetic resonance spectroscopies. 3-(Propionamido)phenylboronic acid (PAPBA) was chosen as the model borate compound. The equilibrium constant (K) for Neu5Ac binding to PAPBA was compared with those for glucose, mannose, and galactose, which are the major carbohydrate constituents of glycoproteins and glycolipids expressed on biological membranes. In the Neu5Ac/PAPBA system, the unusual pH dependency of the K values, a decrease in K with increasing pH, was observed, suggesting the formation of a trigonal-formed complex stabilized by the coordination of an amide group of Neu5Ac at the C-5 position to the boron atom, forming intramolecular B-N or B-O bonding. Furthermore, the anomalously high complexing ability at physiological pH 7.4 was confirmed for this system, with the K value 37.6 which is approximately 7 times higher than that for glucose. This exceptionally high value of K at physiological pH, compared to those of other sugars, strongly suggests that the boronic acid selectively recognizes the Neu5Ac residues of the glycosylated components including glycoproteins and gangliosides existing on the surface of the biological membranes.
“…From the above studies, they concluded that p- TBA or p-BPA formed a complex with three OH groups of β-Dfructofuranose. Shull et al 37 also recently reported on the basis of the 13 C NMR chemical shift and the 1 Jcc coupling method that L-p-BPA formed a complex with β-D-fructofuranose. From the above evidence, it is easy to expect that the boronic acid moiety of PCBA may complex with β-D-fructofuranose, in which the boron atom bound to the three oxygen's at the sites of C2, C3 and C6 of the fructose ring at the physiological pH 7.4, as shown in Structure 1.…”
Section: Complex Formation Between the Boronic Acid Moiety Of Pcba Anmentioning
Boron neutron capture therapy (BNCT) is a form of radiation therapy that has two components. The first is the delivery of boron to a tumor. 1 This can be achieved chemically by boronating a tumor-seeking compound, which is stable in vivo and infused intravenously into a subject body. Then, the boronated compound selectively accumulates sufficient amounts in the tumor cells. The second is to irradiate with thermal neutrons. 1 The capture of a thermal neutron by a 10 B nucleus in a tumor causes the nucleus to split, releasing an α ( 4 He)-particle and a lithium ( 7 Li) nucleus in opposite directions.
2A suitable compound for BNCT must have low toxicity, high solubility in water for rapid injection, and a much higher concentration in the tumor cells than in normal cells. 3 A vast array of 10 B-enriched compounds have been synthesized and tested for BNCT. 4 Among a large number of boron compounds, 10 B-enriched p-carboxybenzeneboronic acid (PCBA) was firstly used in clinical trials as a BNCT agent for some brain-tumor patients. 3 According to those trials, PCBA was one of the most promising compounds as a BNCT drug from the standpoint of the tumor/brain boron ratio, but was found to have relatively high toxicity. 5 The solubility of PCBA is so low at physiological pH 7.4 that it is insufficient for medical uses. This compound dissolves in water by a sufficient amount for injection into patients, at pH 9.4. 6 Therefore, an experiment was carried out as Na-salt of PCBA adjusted as this pH. An injection of this alkaline solution resulted in respiratory depression, seizure, and often the death of some patients. 6,7 The authors suggested that if the solubility of PCBA increased at the physiological pH, then the above mentioned toxicity should be decreased.It is well-known that boric acid 8-10 and pboronophenylalanine (p-BPA) react with monosaccharide to form a soluble anionic complex. 11-13 PCBA has a boronic acid group. Therefore, it can be expected that the boronic acid moiety of PCBA may react with a monosaccharide to form an easily soluble anionic PCBA-monosaccharide complex, as indicated in Eq.(1), which should be recommended as an injection to patients for the BNCT of both brain tumor and malignant melanoma.Boronate anion of PCBA + Monosaccharide Complex.According to the above view, our interest has become involved with the characterization of PCBA ions in solution, and with the formation of soluble anionic complexes between the PCBA ion and a neutral polyhydroxy-compound of monosaccharides at the physiological pH. However, to the best of our knowledge, 11 B NMR studies for both the characterization of PCBA ions and for PCBA complexation with monosaccharides have not been reported so far.In this paper, we wish to describe the chemical behaviors of PCBA ions at various pH, the complex formation equilibria of the PCBA ion with several monosaccharides at the physiological pH based on an investigation of the 11 B NMR spectra, and the possible structure of this complex.
Experimental
ReagentsUnless stated otherwise, all ...
“…The enhanced shielding of 23 ppm, compared to the uncomplexed free boronic acid form, agrees with a tetrahedral boronate and is further in agreement with the shielding found in the tridentate β--fructofuranose 2,3,6-tri-O-(pphenylalanylorthoboronate) compared to the free p-borylphenylalanine. 10 In case of a B-N bound bidentate structure a shielding of only 10-15 should have been expected. 27, 32 Finally, we did two experiments where we added an excess (5 equiv.)…”
The structure of a strong complex between -sorbitol and (S,S)-2-(N,N-dimethyl-1-aminoethyl)ferroceneboronic acid (1) has been determined by NMR spectroscopy. On the basis of 1 H, 13 C and 11 B NMR spectral data, including information from COSY, NOESY and HSQC two-dimensional experiments, a 2,3,5-bound sorbitol complex is deduced. On the basis of coalescence phenomena observed when varying the temperature and pH, an equilibrium between a complex with a covalent and a coordinative B-O5 bond, respectively, is elucidated, and a possible stabilisation of the latter by hydrogen bonding to the amino group is discussed. The existence of intramolecular B-N bonds in 1 and its complexes has been evaluated but no evidence of such bonds was obtained.
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