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Author Notes:

Author Contributions: These authors contributed to this work equally as lead authors. Specific questions regarding the chemistry described herein should be addressed to Ethel Garnier-Amblard at ude.yrome@einrage. Specific questions regarding the in vitro and in vivo assessment described herein should be addressed to Suzanne Mays at ude.yrome@syams.

The assistance of Zhiheng Xu, Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, and Yuan Liu, Winship Cancer Institute Biostatistics Core, Emory University, both of whom performed the statistical analyses utilized in the xenograft studies, is highly appreciated.

Additionally, the early oncolytic studies performed by Dr. Alfred H. Merrill, Jr. and colleagues are equally appreciated, as they served as the foundation for the studies described herein.

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Research Funding:

We gratefully acknowledge financial support from The Emory Institute for Drug Discovery, Emory University.

Keywords:

  • Enigmol
  • palladium cross-coupling
  • 1-deoxysphingoid bases
  • Liebeskind−Srogl reaction
  • prostate cancer therapy
  • PC-3
  • LNCaP

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

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Journal Title:

ACS Medicinal Chemistry Letters

Volume:

Volume 2, Number 6

Publisher:

, Pages 438-443

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2011 American Chemical Society

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