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: joerg.rademann@fu-berlin.de.

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.

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