Synthesis and growth inhibitory properties of glycosides of 1-O-hexadecyl-2-O-methyl-sn-glycerol, analogs of the antitumor ether lipid ET-18-OCH3 (edelfosine).
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.
Marino-Albernas
J R
JR
Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 11367-1597, USA.
Bittman
R
R
Peters
A
A
Mayhew
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D001943:Breast Neoplasms; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D005260:Female; D006027:Glycosides; D006801:Humans; D007202:Indicators and Reagents; D007939:Leukemia L1210; D007941:Leukemia P388; D008175:Lung Neoplasms; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D051379:Mice; D015394:Molecular Structure; D010742:Phospholipid Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006027:Glycosides; D007202:Indicators and Reagents; D010742:Phospholipid Ethers; C026659:edelfosine