Synthesis and evaluation of 3-modified 1D-myo-inositols as inhibitors and substrates of phosphatidylinositol synthase and inhibitors of myo-inositol uptake by cells.
A number of 3-substituted 1D-myo-inositols were synthesized and evaluated as substrates for phosphatidylinositol synthase and uptake by intact cells. 1D-3-Amino-, -3-chloro-, and -3-(acetylthio)-3-deoxy-myo-inositols were all synthesized by nucleophilic displacement of the 6-O-(trifluoromethyl)sulfonyl group of 1L-1,2:3,4-di-O-cyclohexylidene-5-O-methyl-6-O-[(trifluoromethyl)-sulfon yl] - chiro-inositol (which was prepared from L-quebrachitol), respectively, by reaction with LiN3, followed by reduction of the azido function, and with LiCl and KSAc to give the O-protected compounds. O-Demethylation using BBr3 and concomitant acetal hydrolysis furnished the free-hydroxy 3-amino- and 3-chloro-3-deoxy-1D-myo-inositols. The 3-mercapto analogue was obtained by removal of the acetal groups of the acetylthio analogue, followed by acetylation and purification of the peracetate, and subsequent O-demethylation and deacetylation. The 3-deoxy derivative was synthesized from the 6-O-(imidazol-1-ylthiocarbonyl) compound via Barton-McCombie deoxygenation. The 3-azido derivative was directly synthesized from 1L-1-O-tosyl-chiro-inositol via displacement with azide. The 3-keto analogue was prepared by Pt-catalyzed air oxidation of 1L-chiro-inositol. The compounds were all evaluated as substrates for phosphatidylinositol (PtdIns) synthase from mouse brain. The 3-NH2, 3-F, 3-deoxy, and 3-keto analogues all showed activity as substrates, as measured by liberation of cytidine monophosphate. These compounds also showed inhibition of the reaction of myo-[3H]inositol with PtdIns synthase. These results taken together indicate that these compounds are likely to be incorporated into phospholipids. As a further indication that these compounds might be useful as probes for the PtdIns pathway, it was demonstrated that the 3-NH2, 3-F, and 3-deoxy compounds are taken up by intact fibroblast cells as evidenced by their competing with myo-[3H]inositol uptake.
Johnson
S C
SC
Department of Chemistry, University of Tennessee, Knoxville 37996-1600.
Dahl
J
J
Shih
T L
TL
Schedler
D J
DJ
Anderson
L
L
Benjamin
T L
TL
Baker
D C
DC
D000085:Acetates; D000818:Animals; D001386:Azides; D001921:Brain / Q000201:enzymology / Q000648:ultrastructure; D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D007294:Inositol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018021:Lithium Chloride; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000085:Acetates; D001386:Azides; D008565:Membrane Proteins; D007294:Inositol; D017855:Transferases (Other Substituted Phosphate Groups); D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; C496767:Cdipt protein, rat; D018021:Lithium Chloride