Synthesis and Growth Inhibitory Properties of Glycosides of 1-<i>O</i>-Hexadecyl-2-<i>O</i>-methyl-<i>sn</i>-glycerol, Analogs of the Antitumor Ether Lipid ET-18-OCH₃ (Edelfosine)

Abstract

Glycosylated antitumor ether lipids (GAELs), analogs of 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (1, ET-18-OCH3, edelfosine), were synthesized in good overall yields by glycosylation of 1-O-alkyl-2-O-methyl-sn-glycerol and tested for in vitro antineoplastic activity against a variety of murine and human tumor cell lines. Stereospecific glycosylation was achieved by the use of 2-O-acetyl-3,4,6-tri-O-benzylglucopyranosyl and -mannopyranosyl trichloroacetimidates as donors, with trimethylsilyl trifluoromethanesulfonate as catalyst in the presence of molecular sieves at -78 degrees C. The GAELs differ from 1 in having the sn-3-phosphocholine residue replaced by one of the following monosaccharide residues: beta- and alpha-2-deoxy-D-arabino-hexopyranosyl, alpha-D-mannopyranosyl, 2-O-methyl-beta-D-glucopyranosyl, and 2-O-methyl-alpha-D-mannopyranosyl. 1-O-Hexadecyl-2-O-methyl-3-O-(2'-deoxy-beta-D-arabino-hexopyranosyl)- sn-glycerol (2) was more effective than 1 in inhibiting the growth of MCF-7 (human breast cancer) and its adriamycin-resistant form MCF-7/adriamycin, and murine Lewis lung cancer cells. 2-Deoxy-beta-D-arabino-hexopyranoside 2 was also an effective growth inhibitor of two drug-resistant leukemic cell lines, P388/Adr and L1210/vmdr.