Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV-1 activity.
Combinations of an amidoalkylphosphocholine, 8, and AZT have been found to cause an apparent synergistic action in suppressing infectious HIV-1 replication. In addition, amidoalkyl, oxyalkyl, and thioalkyl ether lipids have been chemically linked to anti-HIV-1 nucleosides (AZT and DDI) through phosphate and phosphonate linkages. These conjugates have shown promising in vitro anti-HIV-1 activity. Also, the conjugates have a 5-10-fold reduction in cell cytotoxicity compared to AZT alone. The most active compound, an amidoalkyl ether lipid-AZT conjugates, 4A, was found to have a differential selectivity of 1793 in a syncytial plaque assay. In comparison, AZT alone has a value of 1281.
Piantadosi
C
C
University of North Carolina, School of Pharmacy, Division of Medicinal Chemistry and Natural Products, Chapel Hill 27599.
Marasco
C J
CJ
Morris-Natschke
S L
SL
Meyer
K L
KL
Gumus
F
F
Surles
J R
JR
Ishaq
K S
KS
Kucera
L S
LS
Iyer
N
N
Wallen
C A
CA
D000998:Antiviral Agents / Q000138:chemical synthesis*; D002460:Cell Line; D016049:Didanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054306:Dideoxynucleotides; D004987:Ethers; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007202:Indicators and Reagents; D015394:Molecular Structure; D010742:Phospholipid Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D054306:Dideoxynucleotides; D004987:Ethers; D007202:Indicators and Reagents; D010742:Phospholipid Ethers; C068368:CP 92; D015215:Zidovudine; D016049:Didanosine