NUCLEOSIDE CONJUGATES .15. SYNTHESIS AND BIOLOGICAL-ACTIVITY OF ANTI-HIV NUCLEOSIDE CONJUGATES OF ETHER AND THIOETHER PHOSPHOLIPIDS

A series of the anti-HIV nucleoside conjugates of ether (1-O-alkyl) an d thioether (1-S-alkyl) lipids linked by a pyrophosphate diester bond has been synthesized as micelle-forming prodrugs of the nucleosides to improve their therapeutic efficiency. These include AZT ate-rac-1-S-o ctadecyl-2-O-palmitoyl-1-thioglycerol (1), 3'-azido-2',3'-dideoxyuridi ne ter-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (2), 2',3'-dideo xycytidine ate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (3), and AZT phosphate-rac-1-O-tetradecyl-2-O-palmitoylglycerol (4). The conju gates form micelles by sonication (mean diameters ranging 6.8-55.5 nm) . Conjugate 1 protected 80% of HIV-infected CEM cells as low as 0.58 m u m and lost the protection at 180 mu M due to prevailing cytotoxicity , while the conjugate started to show the cytotoxicity at 100 mu M. Ph armacokinetics studies showed a significant increase of half-life valu es (t(1/2)) of AZT and AZddU(2) (respective t(1/2) = 5.69 and 6.5 h) a fter administration of conjugates 1 and 2, while those after administr ation of AZT and AZddU were 0.28 and 0.89 h, respectively. The fractio ns of the prodrugs 1 and 2 converted to the parent compounds AZT and A ZddU were 36% and 55%, respectively. The results indicate that AZT and AZddU thioether lipid conjugates 1 and 2 warrant further investigatio n.