Substrate properties of analogs of myo-inositol

JD Moyer, O Reizes, S Ahir, C Jiang, N Malinowski and DC Baker

Laboratory of Biological Chemistry, National Cancer Institute, Bethesda, MD 20892.

The hydrolysis of the minor cell membrane lipid phosphatidylinositol- 4,5-bisphosphate mediates the action of many growth factors and hormones. As an approach to the development of specific inhibitors of this process, we have synthesized a series of analogs of myo-inositol and have evaluated their ability to serve as substrates for phosphatidylinositol synthetase. Modification at the 2-, 3-, or 4- positions produced compounds unable to serve as substrates, but several 5-modified analogs retained activity as substrates of phosphatidylinositol synthetase. The product formed from 5-deoxy-5- fluoro-myo-[3H]inositol by phatidylinositol synthetase was hydrolyzed by phospholipase D and gave 5-deoxy-5-fluoro-myo-inositol as the radiolabeled product. Two analogs, 5-deoxy-myo-inositol and 5-deoxy-5- fluoro-myo-inositol, were shown to permeate L1210 leukemia cells and be incorporated into cellular phospholipid. Analysis of the radiolabeled lipids formed on incubation of L1210 cells with 5-deoxy-5-fluoro-myo- [3H]inositol indicated that the fradulent lipid formed was further phosphorylated to the monophosphate but not to the diphosphate form.

Volume 33, Issue 6, pp. 683-689, 06/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics