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Article

Glucosamine-glycerophospholipids That Activate Cell-Matrix Adhesion and Migration

Thilo Bartolmäs, Tabea Heyn, Michael Mickeleit, Annette Fischer, Werner Reutter, and Kerstin Danker*

Institut fr Molekularbiologie und Biochemie, Campus Benjamin Franklin, Charit-Universitaetsmedizin Berlin, Arnimallee 22, D-14195 Berlin-Dahlem, Germany

J. Med. Chem., 2005, 48 (21), pp 6750–6755

DOI: 10.1021/jm050558n

Publication Date (Web): September 14, 2005

For correspondence: phone +49-30-8445 1587; fax +49-30-8445 1541; e-mail kerstin.danker@charite.de.

Abstract

Two new analogues derived from the platelet activating factor (PAF), containing glucosamine instead of the acetyl group, were synthesized, and their effect on the human keratinocyte cell line HaCaT was evaluated with respect to cytotoxicity, proliferation, adhesion, and migration. Starting with (R)-1,2-isopropylideneglycerol (3), the glycosylation acceptor 1-O-octadecyl-3-O-tert-butyldimethylsilyl-sn-glycerol (6) was synthesized in three steps. Glycosylation of 6 with the already known O-(3,4,6-tri-O-acetyl-2-deoxy-2-dimethylmaleimido-β-d-glycopyranosyl)trichloracetimidate gave 1-O-octadecyl-2-O-(3‘,4‘,6‘-tri-O-acetyl-2‘-deoxy-2‘-dimethylmaleimido-β-d-glucopyranosyl)-3-O-tert-butyldimethylsilyl-sn-glycerol (7). After removing the (tert-butyldimethyl)silyl (TBDMS) group with FeCl₃·6H₂O, phosphoryl choline was introduced, yielding [1-O-octadecyl-2-O-(2‘-deoxy-2‘-dimethylmaleimido-β-d-glucopyranosyl)-sn-glycero(3)]phosphorylcholine (2) (glucosimide-PAF). pH controlled cleavage of the amino protection group gave [1-O-octadecyl-2-O-(2‘-deoxy-2‘-amino-β-d-glucopyranosyl)-sn-glycero(3)]phosphorylcholine hydrochloride (1) (glucosamine-PAF). 2 inhibited proliferation of HaCaT cells by 26% at nontoxic concentrations, while 1 increased the proliferation rate by 30% at low concentrations. At higher concentrations, both compounds showed cytotoxic properties with LD₅₀ = 30 μmol/L (1) and LD₅₀ = 5−6 μmol/L (2). Both 1 and 2 were potent promoters of cell adhesion and migration of HaCaT cells.

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Published In Issue October 20, 2005
Received June 13, 2005

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Article

Glucosamine-glycerophospholipids That Activate Cell-Matrix Adhesion and Migration