title: Novel synthesis and biological evaluation of enigmols as therapeutic agents for treating prostate cancer.
abstract: Enigmol is a synthetic, orally active 1-deoxysphingoid base analogue that has demonstrated promising activity against prostate cancer. In these studies, the pharmacologic roles of stereochemistry and N-methylation in the structure of enigmols were examined. A novel enantioselective synthesis of all four possible 2S-diastereoisomers of enigmol (2-aminooctadecane-3,5-diols) from l-alanine is reported, which features a Liebeskind-Srogl cross-coupling reaction between l-alanine thiol ester and (E)-pentadec-1-enylboronic acid as the key step. In vitro biological evaluation of the four enigmol diastereoisomers and 2S,3S,5S-N-methylenigmol against two prostate cancer cell lines (PC-3 and LNCaP) indicates that all but one diastereomer demonstrate potent oncolytic activity. In nude mouse xenograft models of human prostate cancer, enigmol was equally effective as standard prostate cancer therapies (androgen deprivation or docetaxel), and two of the enigmol diastereomers, 2S,3S,5R-enigmol and 2S,3R,5S-enigmol, also caused statistically significant inhibition of tumor growth. A pharmacokinetic profile of enigmol and N-methylenigmol is also presented.
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Ethel C
authors.initials: EC
authors.lastname: Garnier-Amblard
authors.affiliation: School of Medicine, Department of Urology, Emory University , 1365 Clifton Road, NE, Atlanta, Georgia 30322, United States.
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Mays
authors.affiliation: Emory Institute for Drug Discovery (EIDD), 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Arrendale
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Baillie
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Anatoliy S
authors.initials: AS
authors.lastname: Bushnev
authors.affiliation: Emory Institute for Drug Discovery (EIDD), 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Culver
authors.affiliation: Emory Institute for Drug Discovery (EIDD), 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Evers
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Holt
authors.affiliation: Emory Institute for Drug Discovery (EIDD), 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Randy B
authors.initials: RB
authors.lastname: Howard
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Lanny S
authors.initials: LS
authors.lastname: Liebeskind
authors.affiliation: Emory Institute for Drug Discovery (EIDD), 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Menaldino
authors.affiliation: Emory Institute for Drug Discovery (EIDD), 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Natchus
authors.affiliation: School of Medicine, Department of Urology, 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: School of Medicine, Department of Urology, Emory University , 1365 Clifton Road, NE, Atlanta, Georgia 30322, United States.
authors.forename: Harsha
authors.initials: H
authors.lastname: Ramaraju
authors.affiliation: Emory Institute for Drug Discovery (EIDD), 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: G Prabhakar
authors.initials: GP
authors.lastname: Reddy
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive, Atlanta, Georgia 30322, United States ; Emory Institute for Drug Discovery (EIDD), 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
keywords: 1-deoxysphingoid bases; Enigmol; LNCaP; Liebeskind−Srogl reaction; PC-3; palladium cross-coupling; prostate cancer therapy