title: Discovery of a Fluorinated Enigmol Analog with Enhanced in Vivo Pharmacokinetic and Anti-Tumor Properties.
abstract: The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous in vivo settings. However, as no Enigmol analog with enhanced potency in vitro has been identified, a new strategy to improve efficacy in vivo by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel fluorinated Enigmol analogs, CF3-Enigmol and CF2-Enigmol, are reported. Each analog was equipotent to Enigmol in vitro, but achieved higher plasma and tissue levels than Enigmol in vivo. Although plasma and tissue exposures were anticipated to trend with fluorine content, CF2-Enigmol absorbed into tissue at strikingly higher concentrations than CF3-Enigmol. Using mouse xenograft models of prostate cancer, we also show that CF3-Enigmol underperformed Enigmol-mediated inhibition of tumor growth and elicited systemic toxicity. By contrast, CF2-Enigmol was not systemically toxic and demonstrated significantly enhanced antitumor activity as compared to Enigmol.
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive NE, Atlanta, Georgia 30322, United States.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Miller
authors.affiliation: Emory University School of Medicine , Department of Urology, 1365 Clifton Road NE, Atlanta, Georgia 30322, United States.
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Mays
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive NE, Atlanta, Georgia 30322, United States.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Baillie
authors.affiliation: Emory Institute for Drug Development (EIDD) , 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Randy B
authors.initials: RB
authors.lastname: Howard
authors.affiliation: Emory Institute for Drug Development (EIDD) , 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Culver
authors.affiliation: Emory Institute for Drug Development (EIDD) , 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Manohar
authors.initials: M
authors.lastname: Saindane
authors.affiliation: Yerkes National Primate Research Center, Biomarkers Core Laboratory, Emory University , 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Pruett
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive NE, Atlanta, Georgia 30322, United States.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Holt
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive NE, Atlanta, Georgia 30322, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Menaldino
authors.affiliation: Emory Institute for Drug Development (EIDD) , 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Evers
authors.affiliation: Emory Institute for Drug Development (EIDD) , 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: G Prabhakar
authors.initials: GP
authors.lastname: Reddy
authors.affiliation: Emory Institute for Drug Development (EIDD) , 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Arrendale
authors.affiliation: Emory Institute for Drug Development (EIDD) , 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Natchus
authors.affiliation: Emory University School of Medicine, Department of Urology, 1365 Clifton Road NE, Atlanta, Georgia 30322, United States; Emory University School of Medicine, Department of Pathology and Laboratory Medicine, 1364 Clifton Road NE, Atlanta, Georgia 30322, United States; Winship Cancer Institute, Emory University, 1365 Clifton Road NE, Atlanta, Georgia 30322, United States; Atlanta Veterans Affairs Medical Center, Atlanta, Georgia 30033, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Petros
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive NE, Atlanta, Georgia 30322, United States.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
keywords: Enigmol; Sphingolipids; fluorination; prostate cancer