title: Mechanism of Degradation of an α-Keto-Epoxide, a Model for the Warhead for Various Proteasome Inhibitor Anticancer Agents.
abstract: 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.
authors.affiliation: Onyx, a Subsidiary of Amgen, South San Francisco, California 94901.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Phizackerley
authors.affiliation: Onyx, a Subsidiary of Amgen, South San Francisco, California 94901.
authors.forename: Mouhannad
authors.initials: M
authors.lastname: Jumaa
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopalco
authors.affiliation: Onyx, a Subsidiary of Amgen, South San Francisco, California 94901.
authors.forename: Bradley H
authors.initials: BH
authors.lastname: Wolfe
authors.affiliation: Onyx, a Subsidiary of Amgen, South San Francisco, California 94901.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ablan
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047. Electronic address: stella@ku.edu.
authors.forename: Valentino J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D019999:Pharmaceutical Solutions / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D019999:Pharmaceutical Solutions; D061988:Proteasome Inhibitors
keywords: cancer chemotherapy; chemical stability; degradation products; hydrolysis; kinetics; stability; stabilization