Flexible, polymer-supported synthesis of sphingosine derivatives provides ceramides with enhanced biological activity

  • Bioorg Med Chem. 2014 Oct 1;22(19):5506-12. doi: 10.1016/j.bmc.2014.07.024.
Adeeb El-Dahshan  1 ,  Samer I Al-Gharabli  2 ,  Silke Radetzki  1 ,  Taleb H Al-Tel  3 ,  Pradeep Kumar  4 ,  Jörg Rademann  5
Affiliations
  • 1. Leibniz Institute for Molecular Pharmacology (FMP), Robert-Rössle-Str. 10, 13125 Berlin, Germany.
  • 2. Chemical-Pharmaceutical Engineering, School of Applied Medical Sciences, German-Jordanian University, P.O. Box 35247, Amman 11180, Jordan.
  • 3. College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
  • 4. Organic Chemistry Division, National Chemical Laboratory, Homi Bhabha Road, Pune 411 008, India.
  • 5. Institute of Pharmacy, Free University Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany; Leibniz Institute for Molecular Pharmacology (FMP), Robert-Rössle-Str. 10, 13125 Berlin, Germany. Electronic address: [email protected].
PMID: 25172146 DOI: 10.1016/j.bmc.2014.07.024
Abstract

A polymer-supported route for the synthesis of sphingosine derivatives is presented based on the C-acylation of polymeric phosphoranylidene acetates with an Fmoc-protected amino acid. The approach enables the flexible variation of the sphingosine tail through a deprotection-decarboxylation sequence followed by E-selective Wittig olefination cleavage. d-Erythro-sphingosine analogs have been synthesized by diastereoselective reduction of the keto group employing LiAlH(O-tBu)3 as reducing agent. The effect of ceramides and keto-ceramides on the proliferation of three Cancer cell lines HEP G-2, PC-12 and HL-60 was investigated and a ceramide containing an aromatic sphingosine tail was identified as being most active.

Keywords
Apoptosis; Ceramide; Lipid rafts; Lipids; Sphingosine.