Synthesis and Biological Activity of the ᴅ-3-Deoxy-3-fluoro and ᴅ-3-Chloro-3-deoxy Analogues of Phosphatidylinositol

The naturally occurring inositol derivative, ʟ-quebrachitol (1), serves as starting material for the synthesis of ᴅ-3-deoxy-3-fluoro- and ᴅ-3-chloro-3-deoxy-myo-inositol (4,28). Their transformation into the title 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 phosphoramidite protocol, and hydrogenolytic deprotection. Compounds 4 and 28, as reported earlier, exhibit moderate and high selectivity, respectively, in the growth inhibition of -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 possesses a nearly 2 orders of magnitude higher activity but no selectivity 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 CPI is inactive as is the simplified analogue 24 of FPI in which the phosphatidic acid moiety has been replaced by an octadecyl group.