title: Liver S9 Fraction-Derived Metabolites of Curcumin Analogue UBS109.
abstract: To address the shortcomings of the natural product curcumin, many groups have created analogues that share similar structural features while displaying superior properties, particularly in anticancer drug discovery. Relatively unexplored have been the mechanisms by which such compounds are metabolized. A comprehensive in vitro study of a curcumin analogue (UBS109) in liver S9 fractions from five different species is presented. Further, we examine the cell-based bioactivity of the major metabolites. In spite of the fact that UBS109 reduces tumor growth in mice, it is quickly metabolized in vitro and 94% protein bound in mouse plasma. The primary monounsaturated metabolite is only modestly bioactive against MDA-MB-231 breast cancer cells. These observations suggest that while the α,β-unsaturated ketone common to curcumin analogues is important for bioactivity, protein binding and tissue distribution may serve to protect UBS109 from full metabolism in vivo while allowing it to exert a pharmacological effect by means of slow drug release.
authors.affiliation: Department of Chemistry, Emory Institute for Drug Development, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University , Atlanta, Georgia 30322, United States ; Department of Chemistry, Emory Institute for Drug Development, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moore
authors.affiliation: Department of Chemistry, Emory Institute for Drug Development, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhu
authors.affiliation: DMPK Lab, SCYNEXIS, Inc. , Durham, North Carolina 27713, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Randolph
authors.affiliation: Department of Chemistry, Emory Institute for Drug Development, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Shoji
authors.affiliation: Department of Chemistry, Emory Institute for Drug Development, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University , Atlanta, Georgia 30322, United States ; Department of Chemistry, Emory Institute for Drug Development, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
keywords: Curcumin analogue; UBS109; curcumin; liver S9 fraction; metabolism