کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
8514313 1556506 2017 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Mechanism of Degradation of an α-Keto-Epoxide, a Model for the Warhead for Various Proteasome Inhibitor Anticancer Agents
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
پیش نمایش صفحه اول مقاله
Mechanism of Degradation of an α-Keto-Epoxide, a Model for the Warhead for Various Proteasome Inhibitor Anticancer Agents
چکیده انگلیسی
The anticancer agent, carfilzomib, has a unique α-keto-epoxide warhead. The model α-keto-epoxide, N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)pivalamide (1), along with a few of its degradation products was synthesized and studied. The kinetics of hydrolysis and identification of some of the degradation products of 1 were performed at pH values 2, 4, 5, 7, and 8 at 25°C, 40°C, and 60°C and followed by HPLC and liquid chromatography-mass spectroscopy, respectively. 1 degraded independent of pH between pH values 4-7 but showed some acid catalysis at pH 2 and base catalysis at pH 8. Energy of activation, Ea, values progressed from 16.8 ± 0.1 at pH 2 to 20.3 ± 0.1 kcal/mole at pH 8. The major initial degradation products in the pH range 4-5 were the S,R diol (hydrolysis of the epoxide), and S,R chlorohydrin (in the presence of chloride ions). At pH 7-8, the major products were the R,R diastereomer and the S,R and R,R diols. At pH 2, additional unidentified products were seen with relative retention times of 0.28, 0.30, 0.33, and 0.35 and masses equivalent to the diols. The study of 1 provides insight into the degradation of future drugs that use an α-keto-epoxide functional group.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 106, Issue 4, April 2017, Pages 1051-1061
نویسندگان
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