An NMR Study of the Bortezomib Degradation under Clinical Use Conditions
The (R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl-boronic acid, bortezomib (BTZ), which binds the 20S proteasome subunit and causes a large inhibition of its activity, is a peptidomimetic boronic drug mainly used for the treatment of multiple myeloma. Commercial BTZ, stabi...
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| Format: | Article |
| Language: | English |
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Wiley
2009-01-01
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| Series: | Advances in Hematology |
| Online Access: | http://dx.doi.org/10.1155/2009/704928 |
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| author | Adele Bolognese Anna Esposito Michele Manfra Lucio Catalano Fara Petruzziello Maria Carmen Martorelli Raffaella Pagliuca Vittoria Mazzarelli Maria Ottiero Melania Scalfaro Bruno Rotoli |
| author_facet | Adele Bolognese Anna Esposito Michele Manfra Lucio Catalano Fara Petruzziello Maria Carmen Martorelli Raffaella Pagliuca Vittoria Mazzarelli Maria Ottiero Melania Scalfaro Bruno Rotoli |
| author_sort | Adele Bolognese |
| collection | DOAJ |
| description | The (R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl-boronic acid, bortezomib (BTZ), which binds the 20S proteasome subunit and causes a large inhibition of its activity, is a peptidomimetic boronic drug mainly used for the treatment of multiple myeloma. Commercial BTZ, stabilized as mannitol derivative, has been investigated under the common conditions of the clinical use because it is suspected to be easily degradable in the region of its boronic moiety. Commercial BTZ samples, reconstituted according to the reported commercial instructions and stored at 4∘C, were analyzed by high-field nuclear magnetic resonance spectroscopy in comparison with identical samples bubbled with air and argon, respectively. All the samples remained unchanged for a week. After a month, the air filled samples showed the presence of two main degradation products (6% of starting material), the N-(1-(1-hydroxy-3-methylbutylamino)-1-oxo-3-phenylpropan-2-yl) pyrazine-2-carboxamide (BTZ1; 5%, determined from NMR integration) and the (S)-N-(1-(3-methylbutanamido)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide (BTZ2; 1%, determined from NMR integration), identified on the basis of their chemical and spectroscopic properties. The BTZ1 and BTZ2 finding suggests that, under the common condition of use and at 4∘C, commercial BTZ-mannitol is stable for a week, and that, in time, it undergoes slow oxidative deboronation which partially inactivates the product. Low temperature and scarce contact with air decrease the degradation process. |
| format | Article |
| id | doaj-art-56a270b823624fecbb34ff9e7000f00c |
| institution | Kabale University |
| issn | 1687-9104 1687-9112 |
| language | English |
| publishDate | 2009-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advances in Hematology |
| spelling | doaj-art-56a270b823624fecbb34ff9e7000f00c2025-02-03T06:47:24ZengWileyAdvances in Hematology1687-91041687-91122009-01-01200910.1155/2009/704928704928An NMR Study of the Bortezomib Degradation under Clinical Use ConditionsAdele Bolognese0Anna Esposito1Michele Manfra2Lucio Catalano3Fara Petruzziello4Maria Carmen Martorelli5Raffaella Pagliuca6Vittoria Mazzarelli7Maria Ottiero8Melania Scalfaro9Bruno Rotoli10Dipartimento di Chimica Organica e Biochimica, Università Degli Studi di Napoli Federico II, Via Cynthia 6, Monte Sant'Angelo, 80126 Napoli, ItalyDipartimento di Chimica Organica e Biochimica, Università Degli Studi di Napoli Federico II, Via Cynthia 6, Monte Sant'Angelo, 80126 Napoli, ItalyDipartimento di Chimica Organica e Biochimica, Università Degli Studi di Napoli Federico II, Via Cynthia 6, Monte Sant'Angelo, 80126 Napoli, ItalyDipartimento di Biochimica e Biotecnologie Mediche, Divisione di Ematologia, Università Degli Studi di Napoli Federico II, 80131 Napoli, ItalyDipartimento di Biochimica e Biotecnologie Mediche, Divisione di Ematologia, Università Degli Studi di Napoli Federico II, 80131 Napoli, ItalyDipartimento di Biochimica e Biotecnologie Mediche, Divisione di Ematologia, Università Degli Studi di Napoli Federico II, 80131 Napoli, ItalyFarmacia Centralizzata, Azienda Ospedaliera, Universitaria “Federico II”, 80131 Napoli, ItalyFarmacia Centralizzata, Azienda Ospedaliera, Universitaria “Federico II”, 80131 Napoli, ItalyFarmacia Centralizzata, Azienda Ospedaliera, Universitaria “Federico II”, 80131 Napoli, ItalyFarmacia Centralizzata, Azienda Ospedaliera, Universitaria “Federico II”, 80131 Napoli, ItalyDipartimento di Biochimica e Biotecnologie Mediche, Divisione di Ematologia, Università Degli Studi di Napoli Federico II, 80131 Napoli, ItalyThe (R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl-boronic acid, bortezomib (BTZ), which binds the 20S proteasome subunit and causes a large inhibition of its activity, is a peptidomimetic boronic drug mainly used for the treatment of multiple myeloma. Commercial BTZ, stabilized as mannitol derivative, has been investigated under the common conditions of the clinical use because it is suspected to be easily degradable in the region of its boronic moiety. Commercial BTZ samples, reconstituted according to the reported commercial instructions and stored at 4∘C, were analyzed by high-field nuclear magnetic resonance spectroscopy in comparison with identical samples bubbled with air and argon, respectively. All the samples remained unchanged for a week. After a month, the air filled samples showed the presence of two main degradation products (6% of starting material), the N-(1-(1-hydroxy-3-methylbutylamino)-1-oxo-3-phenylpropan-2-yl) pyrazine-2-carboxamide (BTZ1; 5%, determined from NMR integration) and the (S)-N-(1-(3-methylbutanamido)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide (BTZ2; 1%, determined from NMR integration), identified on the basis of their chemical and spectroscopic properties. The BTZ1 and BTZ2 finding suggests that, under the common condition of use and at 4∘C, commercial BTZ-mannitol is stable for a week, and that, in time, it undergoes slow oxidative deboronation which partially inactivates the product. Low temperature and scarce contact with air decrease the degradation process.http://dx.doi.org/10.1155/2009/704928 |
| spellingShingle | Adele Bolognese Anna Esposito Michele Manfra Lucio Catalano Fara Petruzziello Maria Carmen Martorelli Raffaella Pagliuca Vittoria Mazzarelli Maria Ottiero Melania Scalfaro Bruno Rotoli An NMR Study of the Bortezomib Degradation under Clinical Use Conditions Advances in Hematology |
| title | An NMR Study of the Bortezomib Degradation under Clinical Use Conditions |
| title_full | An NMR Study of the Bortezomib Degradation under Clinical Use Conditions |
| title_fullStr | An NMR Study of the Bortezomib Degradation under Clinical Use Conditions |
| title_full_unstemmed | An NMR Study of the Bortezomib Degradation under Clinical Use Conditions |
| title_short | An NMR Study of the Bortezomib Degradation under Clinical Use Conditions |
| title_sort | nmr study of the bortezomib degradation under clinical use conditions |
| url | http://dx.doi.org/10.1155/2009/704928 |
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