Synthesis and biological activity of novel quaternary ammonium derivatives of alkylglycerols as potent inhibitors of protein kinase C

• Published in: Journal of medicinal chemistry Vol. 33; no. 3; pp. 985 - 992
• Main Authors: Marasco, Canio J, Piantadosi, Claude, Meyer, Karen L, Morris-Natschke, Susan, Ishaq, Khalid S, Small, George W, Daniel, Larry W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-03-1990
• Subjects: Aliphatic compounds; alkylglycerols; ammonium; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Chemistry; Diglycerides - pharmacology; Exact sciences and technology; Humans; Organic chemistry; Phosphatidylserines - pharmacology; Phospholipid Ethers - chemical synthesis; Phospholipid Ethers - pharmacology; Preparations and properties; Protein Kinase C - antagonists & inhibitors; Structure-Activity Relationship; Antineoplastic agent; Protein kinase C; Organic cation; Ether; Aliphatic compound; Saturated compound; Enzyme inhibitor; Biological activity; Organic sulfide
• DOI: 10.1021/jm00165a016
• EISSN: 1520-4804
• ISSN: 0022-2623

Alkylglycerols such as rac-1-O-octadecyl-2-O-methylglycerophosphochocholine (Et-18-OMe) have shown an inhibitory effect on the metastasis and growth of various cancer cell lines. Alkyl phospholipids have been shown to accumulate at the surface in several cell lines, the selectivity of which is still not clearly understood. A consequence of this action may lead to the inhibition of cell membrane related protein kinase C (PKC). The goal of this research was to develop ether lipid inhibitors of PKC to augment antineoplastic activity. This led to the synthesis and in vitro testing of a series of novel quaternary ammonium derivatives of alkylglycerols. The biological testing of these analogues on PKC stimulated with rac-1-O-oleoyl-2-O-acetylglycerol showed several analogues with inhibition comparable to that of Et-18-OMe.