Glucosamine-glycerophospholipids that activate cell-matrix adhesion and migration.
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-beta-D-glycopyranosyl)trichloracetimidate gave 1-O-octadecyl-2-O-(3',4',6'-tri-O-acetyl-2'-deoxy-2'-dimethylmaleimido-beta-D-glucopyranosyl)-3-O-tert-butyldimethylsilyl-sn-glycerol (7). After removing the (tert-butyldimethyl)silyl (TBDMS) group with FeCl3x6H2O, phosphoryl choline was introduced, yielding [1-O-octadecyl-2-O-(2'-deoxy-2'-dimethylmaleimido-beta-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-beta-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 micromol/L (1) and LD50 = 5-6 micromol/L (2). Both 1 and 2 were potent promoters of cell adhesion and migration of HaCaT cells.
Bartolmäs
Thilo
T
Institut für Molekularbiologie und Biochemie, Campus Benjamin Franklin, Charité-Universitaetsmedizin Berlin, Arnimallee 22, D-14195 Berlin-Dahlem, Germany.
Heyn
Tabea
T
Mickeleit
Michael
M
Fischer
Annette
A
Reutter
Werner
W
Danker
Kerstin
K
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002448:Cell Adhesion / Q000187:drug effects*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D020404:Glycerophospholipids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006017:Glycolipids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D013329:Structure-Activity Relationship
C505983:(1-O-octadecyl-2-O-(2'-deoxy-2'-aminoglucopyranosyl)glycerol(3))phosphorylcholine; C505984:(1-O-octadecyl-2-O-(2'-deoxy-2'-dimethylmaleimidoglucopyranosyl)glycerol(3))phosphorylcholine; D000970:Antineoplastic Agents; D020404:Glycerophospholipids; D006017:Glycolipids; D005944:Glucosamine