Synthesis, activity and toxicity of novel macrocyclic ligands against HIV-1 in Jurkat and CEM-SS cell lines.
We have developed versatile synthetic routes that afford metal-free macrocycles containing different functionalities in their framework. Novel oxaziridine and amide containing macrocycles were synthesized, and the metal complexes of the latter were also prepared. A series of theophilline and thymidine side-arm containing podands as well as macrocycles were obtained employing the same methodology. The primary anti-viral tests of these synthetic compounds for anti-HIV-1 activity was carried out using the XTT-based cytopathicity assay (CEM-SS cells) with AZT as positive control. It was found that the nature of the macrocyclic headgroups affected the anti-HIV-1 activity. Heteroatom containing macrocyclic headgroups displayed activity in the micromolar range. Metal complexation did not enhance the activity and side-arm substitution resulted in inactive compounds. Cell viability determined in both Jurkat and CEM-SS cells was strongly dependent on the structure of the macrocyclic framework. The oxaziridine moieties in the macrocycle were highly toxic to CEM-SS and less toxic to Jurkat cell lines, while amide containing macrocycles were toxic to neither.
Balogh-Nair
V
V
Department of Chemistry, City College of New York, CUNY 10031, USA.
Brathwaite
C E
CE
Chen
C X
CX
Vargas
J
J
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001388:Aziridines / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D008024:Ligands; D015394:Molecular Structure; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D001388:Aziridines; D001559:Benzhydryl Compounds; D006571:Heterocyclic Compounds; D008024:Ligands