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Mechanism of Degradation of an -Keto-Epoxide, a Model for the Warhead for Various Proteasome Inhibitor Anticancer Agents

Phizackerley, Kirsten and Jumaa, Mouhannad and Lopalco, Antonio and Wolfe, Bradley H. and Ablan, Christopher D. and Stella, Valentino J. (2017) Mechanism of Degradation of an -Keto-Epoxide, a Model for the Warhead for Various Proteasome Inhibitor Anticancer Agents. Journal of pharmaceutical sciences, 106. pp. 1051-1061.

Abstract

The anti-cancer agent, carfilzomib has a unique -keto-epoxide warhead. The model -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 were 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 LC-MS, respectively. 1 degraded independent of pH between pH values 4 to 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 (RRT) 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 utilize an -keto-epoxide functional group.

Item Type: Article
Keywords: Degradation products, Stability, Stabilization, Kinetics, Chemical Stability, Hydrolysis, Cancer Chemotherapy
Date Deposited: 29 Mar 2017 00:45
Last Modified: 29 Mar 2017 00:45
URI: https://oak.novartis.com/id/eprint/31621

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