Ether phospholipid-AZT conjugates possessing anti-HIV and antitumor cell activity. Synthesis, conformational analysis, and study of their thermal effects on membrane bilayers.
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.
Mavromoustakos
T
T
National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, Vas. Constantinou 48, 116 35, Athens, Greece.
Calogeropoulou
T
T
Koufaki
M
M
Kolocouris
A
A
Daliani
I
I
Demetzos
C
C
Meng
Z
Z
Makriyannis
A
A
Balzarini
J
J
De Clercq
E
E
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002152:Calorimetry, Differential Scanning; D002478:Cells, Cultured; D054306:Dideoxynucleotides; D004354:Drug Screening Assays, Antitumor; D005990:Glycerol / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry; D012996:Solutions; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D013937:Thymidine Kinase / Q000172:deficiency; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C427732:3'-azido-3'-deoxythymidine 5'-(3-(1-O-hexadecyl-2-O-methylglycerol)phosphate); C427733:3'-azido-3'-deoxythymidine 5'-(O-hexadecyl)phosphate; D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D054306:Dideoxynucleotides; D008051:Lipid Bilayers; D009705:Nucleosides; D012996:Solutions; D015215:Zidovudine; D013937:Thymidine Kinase; D005990:Glycerol