IN-VITRO EVALUATION AND CHARACTERIZATION OF NEWLY DESIGNED ALKYLAMIDOPHOSPHOLIPID ANALOGS AS ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 AGENTS

Our laboratories first reported two novel classes of complex synthetic lipids, including alkylamidophosphocholines (PC lipid; CP-51) and alk ylamidophosphate ester-linked lipid-AZT conjugates (lipid-AZT conjugat es; CP-92), with selective and potent activity against human immunodef iciency virus type 1 (HIV-1). To extend these observations, we synthes ized additional PC lipids and lipid-AZT conjugates (INK and INK-AZT co njugate) 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 bon e marrow cells. PC lipid compounds with medium chain lengths at positi ons 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 selec tive when evaluated in CEM-SS cells. INK-14, a lipid-AZT conjugate whe re 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 li pid 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-res istant HIV-1 clinical isolates. INK-3 also inhibited replication of HI V-2 and TIBO-resistant HIV-1, and inhibited HIV-1-mediated fusogenic a ctivity by 78, 41 and 9% in a dose-dependent manner. The TC50 for mous e bone marrow cells was >100 mu g/ml for INK-3 compared to 9.15-14.17 mu g/ml for CP-51 and 0.142-0.259 mu g/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.