Degradation of paclitaxel and related compounds in aqueous solutions II: Nonepimerization degradation under neutral to basic pH conditions
Degradation of paclitaxel and related compounds in aqueous solutions II: Nonepimerization degradation under neutral to basic pH conditions
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DOI：
10.1002/jps.21214
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发表时间：
2008-08-01
影响因子：
3.8
通讯作者：
Stella, Valentino J.
中科院分区：
文献类型：
--
作者：
Tian, Jiaher;Stella, Valentino J.
紫杉醇和其他紫杉烷具有复杂的结构，包括许多水解敏感的酯基的存在。本研究试图通过研究紫杉醇中各种酯基的水解动力学，同时也研究了7-epi-紫杉醇、10-去乙酰紫杉醇、7-epi-10-去乙酰紫杉醇、baccatin III、10-deacetylbaccatin III和n -苯甲酰-3-苯基异丝氨酸乙酯的水解。研究了pH、缓冲液浓度和温度对降解动力学的影响，并采用稳定性指示HPLC法和LC/MS法对降解产物进行了分析。在7位发生的外映反应使动力学变得复杂，但可以分离出动力学的水解组分。正如预期的那样，在pH 6-7以上观察到的所有酯水解反应都是碱催化的。在C7处外映化后，紫杉醇水解主要是侧链的断裂，C10、C2和C4处的酯键进一步水解，而C10醋酸酯的水解相对来说是次容易的。通过研究10-去乙酰紫杉醇、7-外延-10-去乙酰紫杉醇、baccatin III、10-去乙酰baccatin III和n -苯甲酰-3-苯基异丝氨酸乙酯的水解，可以更好地了解更大更复杂紫杉醇的水解。(C) 2007 Wiley-Liss, Inc.和美国药剂师协会。
Paclitaxel and other taxanes have complex structures that include the presence of numerous hydrolytically sensitive ester groups. The present study attempts to make sense of the kinetics of the base catalyzed hydrolysis of various ester groups found in paclitaxel by also studying the hydrolysis of 7-epi-taxol, 10-deacetyltaxol, 7-epi-10-deacetyltaxol, baccatin III, 10-deacetylbaccatin III and N-benzoyl-3-phenylisoserine ethyl ester. Kinetics were studied as function of pH, buffer concentration and temperature, and analyzed using a stability indicating HPLC assay and LC/MS to identify degradation products. The kinetics were complicated by the epimerization reaction occurring at the 7-position but isolation of the hydrolytic components of the kinetics was possible. All ester hydrolysis reactions observed above pH 6-7 were, as expected, base catalyzed. After epimerization at the C7, paclitaxel hydrolysis occurs mainly due to cleavage of the side chain with further hydrolysis of the ester bonds at C10, C2 and C4 with the C10 acetate hydrolysis being the relatively next most facile. By studying the hydrolysis of 10-deacetyltaxol, 7-epi-10-deacetyltaxol, baccatin III, 10-deacetylbaccatin III and N-benzoyl-3-phenylisoserine ethyl ester, good insight into the hydrolysis of the larger more complex taxanes was possible. (C) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.