title: In vitro evaluation and characterization of newly designed alkylamidophospholipid analogues as anti-human immunodeficiency virus type 1 agents.
abstract: Our laboratories first reported two novel classes of complex synthetic lipids, including alkylamidophosphocholines (PC lipid; CP-51) and alkylamidophosphate ester-linked lipid-AZT conjugates (lipid-AZT conjugates; CP-92), with selective and potent activity against human immunodeficiency virus type 1 (HIV-1). To extend these observations, we synthesized additional PC lipids and lipid-AZT conjugates (INK and INK-AZT conjugate) to evaluate their structure-activity relationships by testing for selectivity against infectious wild-type (wt) and drug-resistant HIV-1 replication, virus fusogenic activity and toxicity for mouse bone marrow cells. PC lipid compounds with medium chain lengths at positions 1 and 2 gave an improved selective index (SI). INK-3, with 12 and 8 carbons and INK-15, with 10 and 12 carbons were among the most selective when evaluated in CEM-SS cells. INK-14, a lipid-AZT conjugate where AZT replaced the choline in PC lipid INK-3, gave the highest SI of > 1250 against both infectious wt HIV-1 replication in CEM-SS cells and a clinical isolate in peripheral blood leukocytes. Notably, the PC lipid compounds INK-3 and INK-15, but not the lipid-AZT conjugate INK-14, were potent inhibitors of matched pairs of AZT-sensitive and AZT-resistant HIV-1 clinical isolates. INK-3 also inhibited replication of HIV-2 and TIBO-resistant HIV-1, and inhibited HIV-1-mediated fusogenic activity by 78, 41 and 9% in a dose-dependent manner. The TC50 for mouse bone marrow cells was > 100 micrograms/ml for INK-3 compared to 9.15-14.17 micrograms/ml for CP-51 and 0.142-0.259 microgram/ml for AZT. These data suggest that optimum PC lipid compounds are significantly less toxic than AZT and have high potential as novel therapeutic agents for AIDS.
authors.affiliation: Wake Forest University School of Medicine, Winston-Salem, N.C., USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Kucera
authors.forename: N
authors.initials: N
authors.lastname: Iyer
authors.forename: S L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: S Y
authors.initials: SY
authors.lastname: Chen
authors.forename: F
authors.initials: F
authors.lastname: Gumus
authors.forename: K
authors.initials: K
authors.lastname: Ishaq
authors.forename: D B
authors.initials: DB
authors.lastname: Herrmann
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D002460:Cell Line; D004341:Drug Evaluation; D004352:Drug Resistance, Microbial; D005260:Female; D015726:Giant Cells / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008561:Membrane Fusion / Q000187:drug effects; D051379:Mice; D010743:Phospholipids / Q000737:chemistry / Q000494:pharmacology*; D010948:Viral Plaque Assay; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D010743:Phospholipids; D015215:Zidovudine