Ether phospholipid-AZT conjugates possessing anti-HIV and antitumor cell activity. Synthesis, conformational analysis, and study of their thermal effects on membrane bilayers.

Abstract

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

• Authors: T Mavromoustakos, T Calogeropoulou, M Koufaki, A Kolocouris, I Daliani, C Demetzos, Z Meng, A Makriyannis, J Balzarini, E De Clercq
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 44 Issue 11 Pg. 1702-9 (May 24 2001) ISSN: 0022-2623 [Print] United States
• PMID: 11356105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3'-azido-3'-deoxythymidine 5'-(3-(1-O-hexadecyl-2-O-methylglycerol)phosphate)
• 3'-azido-3'-deoxythymidine 5'-(O-hexadecyl)phosphate
• Anti-HIV Agents
• Antineoplastic Agents
• Dideoxynucleotides
• Lipid Bilayers
• Nucleosides
• Solutions
• Zidovudine
• Thymidine Kinase
• Glycerol

Topics

• Animals
• Anti-HIV Agents (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Calorimetry, Differential Scanning
• Cells, Cultured
• Dideoxynucleotides
• Drug Screening Assays, Antitumor
• Glycerol (chemistry)
• HIV-1 (drug effects)
• HIV-2 (drug effects)
• Humans
• Lipid Bilayers (chemistry)
• Magnetic Resonance Spectroscopy
• Mice
• Models, Molecular
• Molecular Conformation
• Nucleosides (chemistry)
• Solutions
• T-Lymphocytes (drug effects, virology)
• Thymidine Kinase (deficiency)
• Zidovudine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)