| Abstract
| - The 1-O-hexadecyl-2-O-methyl-sn-glyceryl phosphodiester AZT 4 and hexadecyl-phosphodiesterAZT 5 derivatives were synthesized and found to be active against HIV-1, HIV-2, and tumorcell proliferation. Compared to AZT, compound 4 possessed ca. 10-fold lower anti-HIV activityand ca. 10-fold higher anti-tumor cell activity. Compound 5 was 10-fold less potent thancompound 4 in both biological tests. In an attempt to correlate biological activity of compounds4 and 5 with structure, their conformational and thermal effects on membrane bilayers werecompared using a combination of NMR spectroscopy, computational analysis, and DifferentialScanning Calorimetry. The obtained results showed that compound 4 adopts a compactconformation in which the alkyl chain, the 2-methoxyglyceryl functionality, and the methylgroup of thymine are in spatial proximity, while analogue 5 possesses a less compactconformation of the nucleoside base and the alkyl chain. The presence of the 2-methoxyglycerylgroup in compound 4 may augment its potency by inducing a turn of the alkyl chain stabilizedby hydrophobic interactions. The DSC scans show that conjugate 4 affects less effectively thethermotropic properties of model membrane bilayers than compound 5. This may be attributedto the fact that compound 4 is incorporated in a compact conformation and does not perturbsignificantly the trans:gauche isomerization of the membrane phospholipids. In contrast,conjugate 5 may enter with a less compact conformation and perturb more the membranebilayers.
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