title: In vitro evaluation of phosphocholine and quaternary ammonium containing lipids as novel anti-HIV agents.
abstract: A series of synthetic lipids containing a two- or three-carbon backbone substituted with a thio, oxy, or amidoalkyl functionality and either a phosphocholine or quaternary ammonium moiety was evaluated as potential anti-HIV-1 agents. Several analogues were identified as possessing activity with the most promising compound being rac-3-octadecanamido-2-ethoxypropylphosphocholine (8). Compound 8 exhibited an IC50 for the inhibition of plaque formation of 0.16 microM which was 84-fold lower than the IC50 value determined for CEM-SS cell growth inhibition. Initial mechanistic studies have indicated that these compounds, unlike AZT, are not reverse transcriptase (RT) inhibitors, but instead appear to inhibit a late step in HIV replication involving virus assembly and infectious virus production. Since these lipids are acting via a different mechanism, they represent an alternative approach to the chemotherapeutic treatment of AIDS as well as candidates for combination therapy with AZT.
authors.affiliation: University of North Carolina, School of Pharmacy, Division of Medicinal Chemistry and Natural Products, Chapel Hill 27599.
authors.forename: K L
authors.initials: KL
authors.lastname: Meyer
authors.forename: C J
authors.initials: CJ
authors.lastname: Marasco
authors.forename: S L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: K S
authors.initials: KS
authors.lastname: Ishaq
authors.forename: C
authors.initials: C
authors.lastname: Piantadosi
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010742:Phospholipid Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D007202:Indicators and Reagents; D010742:Phospholipid Ethers; D000644:Quaternary Ammonium Compounds; C068367:3-octadecanamido-2-ethoxypropylphosphocholine; D015215:Zidovudine