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

Shull, Brian K.; Spielvogel, David E.; Head, Gerald; Gopalaswamy, Ramesh; Sankar, S. S.; Devito, Kevin

doi:10.1002/(sici)1520-6017(200002)89:2<215::aid-jps8>3.0.co;2-p

Cited by 31 publications

(10 citation statements)

References 34 publications

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“…[3][4][5] The solubility of bortezomib in water is about 0.5-0.6 mg/mL, whereas in the presence of 1% mannitol, a solubility of 4 mg/mL has been reported because of ester formation. 4,5 Except for the work of Yan et al, Springsteen and Wang, and a few others, [9][10][11][12][13][14][15][16] relatively limited quantitative information on boronic acid ester formation with 1,2-diols is available. However, the interaction of boronic acid derivatives and sugars has long been used for separation and analytical purposes as well as in designing drug delivery devices, especially those used to sense glucose changes.…”

Section: Introductionmentioning

confidence: 99%

“…Except for the work of Yan et al, Springsteen and Wang, and a few others, relatively limited quantitative information on boronic acid ester formation with 1,2‐diols is available. However, the interaction of boronic acid derivatives and sugars has long been used for separation and analytical purposes as well as in designing drug delivery devices, especially those used to sense glucose changes.…”

Section: Introductionmentioning

confidence: 99%

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Interaction of Model Aryl- and Alkyl-Boronic Acids and 1,2-Diols in Aqueous Solution

Marinaro

Prankerd

Kinnari

et al. 2015

Journal of Pharmaceutical Sciences

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interaction of Model Aryl- and Alkyl-Boronic Acids and 1,2-Diols in Aqueous Solution

Marinaro

Prankerd

Kinnari

et al. 2015

Journal of Pharmaceutical Sciences

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“…The original manuscripts8,9 investigating BPA–saccharide mixtures for clinical use did not report any effect on the p K a values on the addition of fructose or mannitol; however, a reduction in the p K a values of the boronic acid group (more specifically, the boronic acid–fructose complex) in phenylboronic acid from 8.8 to 4.6 on complexation with fructose has been previously reported 20. The shift in the p K a of the boronic acid group of BPA in the presence of mannitol or fructose can be explained by the formation of the previously described tetrahedral anionic complex of BPA and monosaccharide, decreasing the oxygen–boron–oxygen bond angle which increases the acidity of the boron centre 21,22. These results also illustrate that the complexation involves or influences the carboxylic acid group causing its p K a to increase, a feature which, again, has not been previously demonstrated for BPA–fructose complexes 22.…”

Section: Discussionmentioning

confidence: 86%

“…The shift in the p K a of the boronic acid group of BPA in the presence of mannitol or fructose can be explained by the formation of the previously described tetrahedral anionic complex of BPA and monosaccharide, decreasing the oxygen–boron–oxygen bond angle which increases the acidity of the boron centre 21,22. These results also illustrate that the complexation involves or influences the carboxylic acid group causing its p K a to increase, a feature which, again, has not been previously demonstrated for BPA–fructose complexes 22. HPCD does not influence the measured p K a values of boronic acid, indicating that it does not interact with BPA through the boronic acid group in the same way as the monosaccharides.…”

Section: Discussionmentioning

confidence: 93%

Physicochemical Investigation of the Influence of Saccharide-Based Parenteral Formulation Excipients on l-p-Boronphenylalanine Solubilisation for Boron Neutron Capture Therapy

Schmidt

Dooley

Ford

et al. 2012

Journal of Pharmaceutical Sciences

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This paper investigates the physicochemical properties of possible pharmaceutical alternatives to L-p-boronphenylalanine (BPA)-fructose intravenous formulation currently employed in boron neutron capture therapy. The physicochemical properties of BPA in the absence and presence of fructose, mannitol, trehalose and hydroxypropyl-β-cyclodextrin (HPCD) was investigated by determination of pKa values, solubility, precipitation and dissolution using a Sirius T3 instrument. Complex formation was also assessed using (10) B-Nuclear magnetic resonance (NMR). The results indicate that fructose and mannitol form a complex with BPA through a reversible interaction with the boronic acid group, determined by changes in the pKa of the boronic acid group, the ultraviolet and NMR spectra, and increase in kinetic solubility. Trehalose and HPCD did not undergo this reaction and, consequently, did not affect boronphenylalanaine physicochemical properties. Although mannitol is complexed with BPA in an identical manner to fructose, it is superior because it provides increased kinetic solubility. Replacement of fructose by mannitol in the current clinical BPA formulation is, therefore, feasible with advantages of increased dosing and removal of issues related to fructose intolerance and calorific load. Results also indicated that important pharmaceutical parameters are the complex's solubility and dissociation behaviours rather than, as originally assumed, the complex formation reaction.

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“…Another possibility on improving CCB-2 solubility is using of monosaccharide or sugar alcohol, which is successfully applied for Boronophenylalanine (L-BPA) and PGB-0 (Shull et al, 2000;Susidarti et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The Evaluation of Cytotoxic Properties from CCB-2 Sugar Complexes Against TNBC and Non-TNBC Cells

Jenie

Utomo

Susidarti

et al. 2021

Asian Pac J Cancer Prev

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Objective: The progress from Boron Neutron Capture Therapy (BNCT) development urged us to explore new targeted and selective boron carriers. Firstly, we reported the successful synthesis of CCB-2 which exerts a cytotoxic effect against triple negative breast cancer (TNBC) cells. We introduced the new modification of CCB-2 with sugar and alcohol sugars to enhance its solubility in hoping to increase cellular uptake. Methods: CCB-2 fructose complex (CCB-2-F), CCB-2 sorbitol complex (CCB-2-Sor), and CCB-2 xylitol complex (CCB-2-Xy) were obtained with small size within nano-specific particle. All the compounds were then determined for their cytotoxic activities through MTT assay. Results: All compounds were performed cytotoxic activities against TNBC 4T1 and HER-2 positive MCF-7/ HER2 cells with good selectivity when tested in immortalized fibroblast cells. Conclusion: Overall, we provided a new modification of CCB-2 through complexation with sugars. Still, further evaluations are needed to develop more efficient CCB-2 as the new candidate of anticancer agent, notably in breast cancer.

show abstract

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

Cited by 31 publications

References 34 publications

Interaction of Model Aryl- and Alkyl-Boronic Acids and 1,2-Diols in Aqueous Solution

Interaction of Model Aryl- and Alkyl-Boronic Acids and 1,2-Diols in Aqueous Solution

Physicochemical Investigation of the Influence of Saccharide-Based Parenteral Formulation Excipients on l-p-Boronphenylalanine Solubilisation for Boron Neutron Capture Therapy

The Evaluation of Cytotoxic Properties from CCB-2 Sugar Complexes Against TNBC and Non-TNBC Cells

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