Bolognese Adele, Esposito Anna, Manfra Michele, Catalano Lucio, Petruzziello Fara, Martorelli Maria Carmen, Pagliuca Raffaella, Mazzarelli Vittoria, Ottiero Maria, Scalfaro Melania, Rotoli Bruno
Dipartimento di Chimica Organica e Biochimica, Università Degli Studi di Napoli Federico II, Via Cynthia 6, Monte Sant'Angelo, 80126 Napoli, Italy.
Adv Hematol. 2009;2009:704928. doi: 10.1155/2009/704928. Epub 2009 Apr 14.
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 degrees 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 degrees 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.
（R）-3-甲基-1-（（S）-3-苯基-2-（吡嗪-2-甲酰胺基）丙酰胺基）丁基硼酸硼替佐米（BTZ），它与20S蛋白酶体亚基结合并导致其活性大幅抑制，是一种主要用于治疗多发性骨髓瘤的拟肽硼酸药物。作为甘露醇衍生物稳定化的市售BTZ，因其硼酸部分在临床使用的常见条件下可能易于降解而受到研究。按照报告的商业说明复溶并储存在4℃的市售BTZ样品，分别与用空气和氩气鼓泡的相同样品进行比较，通过高场核磁共振光谱分析。所有样品在一周内保持不变。一个月后，充空气的样品显示存在两种主要降解产物（起始原料的6%），N-（1-（1-羟基-3-甲基丁基氨基）-1-氧代-3-苯基丙烷-2-基）吡嗪-2-甲酰胺（BTZ1；5%，由NMR积分测定）和（S）-N-（1-（3-甲基丁酰胺基）-1-氧代-3-苯基丙烷-2-基）吡嗪-2-甲酰胺（BTZ2；1%，由NMR积分测定），根据它们的化学和光谱性质鉴定。BTZ1和BTZ2的发现表明，在常见使用条件和4℃下，市售BTZ-甘露醇在一周内是稳定的，并且随着时间的推移，它会发生缓慢的氧化脱硼反应，使产物部分失活。低温和与空气的接触减少会降低降解过程。
