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.