Novel Synthesis and Biological Evaluation of Enigmols as Therapeutic Agents for Treating Prostate Cancer

• Authors: Ethel C. Garnier-Amblard, Emory University; Suzanne G. Mays, Emory University; Richard Franklin Arrendale, Emory University; Mark T. Baillie, Emory University; Anatoliy S. Bushnev, Emory University; Deborah Culver, Emory Institute for Drug Discovery; Taylor J. Evers, Emory Institute for Drug Discovery; Jason J. Holt, Emory University; Randy B. Howard, Emory Institute for Drug Discovery; Lanny S Liebeskind, Emory University; David Menaldino, Emory University; Michael George Natchus, Emory University; John A Petros, Emory University; Harsha Ramaraju, Emory University; Prabhakar Reddy Gruddanti, Emory University; Dennis C Liotta, Emory University
• Journal Title: ACS Medicinal Chemistry Letters
• Volume: Volume 2, Number 6
• Publisher: American Chemical Society | 2011-06-09, Pages 438-443
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1021/ml2000164
• Subjects: Chemistry, Pharmaceutical; Health Sciences, Oncology; Health Sciences, General
• Keywords: Enigmol; palladium cross-coupling; 1-deoxysphingoid bases; Liebeskind−Srogl reaction; prostate cancer therapy; PC-3; LNCaP

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.