SYNTHESIS AND BIOLOGICAL-ACTIVITY OF THE D-3-DEOXY-3-FLUORO AND D-3-CHLORO-3-DEOXY ANALOGS OF PHOSPHATIDYLINOSITOL

The naturally occurring inositol derivative, L-quebrachitol (1), serve s as starting material for the synthesis of D-3-deoxy-3-fluoro- and D- 3-chloro-3-deoxy-myo-inositol (4, 28). Their transformation into the t itle compounds 22 and 40 (abbreviated as FPI and CPI, respectively) is accomplished by benzylation of all hydroxyl groups but OH-1 to which the phosphatidic acid side chain is subsequently attached using the ph osphoramidite protocol, and hydrogenolytic deprotection. Compounds 4 a nd 28, as reported earlier, exhibit moderate and high selectivity, res pectively, in the growth inhibition of v-sis transformed vs wild type murine NIH 3T3 cells if myo-inositol is absent but are inactive in the presence of physiological inositol levels. On the other hand, FPI pos sesses a nearly 2 orders of magnitude higher activity but no selectivi ty both in the absence or presence of myo-inositol. CPI is inactive as is the simplified analogue 24 of FPI in which the phosphatidic acid m oiety has been replaced by an octadecyl group.