Synthesis and antiretroviral evaluation of new alkoxy and aryloxy phosphate derivatives of 3'-azido-3'-deoxythymidine.
A series of new ether lipid-3'-azido-3'-deoxythymidine (AZT) conjugates (11a-g) were synthesized and evaluated for anti-HIV activity. The effect of chirality on the antiviral activity was examined through the synthesis of AZT conjugates bearing alkoxypropanols in the lipid portion of the molecule (11a-d). In addition, the long alkyl chain of alkoxyethyl ether lipid-AZT analogs was replaced with aromatic groups (11e-g), and the effect of this structural modification on activity is reported. The results of the biological tests indicate that analogs with a methyl group alpha to the phosphate moiety (11c,d) exhibit a marked degree of stereoselectivity with regard to their anti-HIV activity. Also, replacement of the long alkyl chain with aromatic groups in the oxyalkyl ether phospholipid-AZT conjugates leads to substantially more potent compounds (11e-g) with an anti-HIV activity comparable to that of AZT.
Tsotinis
A
A
Department of Pharmacy, University of Athens, Panepistimiopoli Zografou, Greece.
Calogeropoulou
T
T
Koufaki
M
M
Souli
C
C
Balzarini
J
J
De Clercq
E
E
Makriyannis
A
A
D000478:Alkylation; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010743:Phospholipids; D012190:Retroviridae / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D000998:Antiviral Agents; D010743:Phospholipids; D015215:Zidovudine