SYNTHESIS, ACTIVITY AND TOXICITY OF NOVEL MACROCYCLIC LIGANDS AGAINSTHIV-1 IN JURKAT AND CEM-SS CELL-LINES

We have developed versatile synthetic routes that afford metal-free ma crocycles containing different functionalities in their framework. Nov el oxaziridine and amide containing macrocycles were synthesized, and the metal complexes of the latter were also prepared. A series of theo philline and thymidine side-arm containing podands as well as macrocyc les were obtained employing the same methodology. The primary anti-vir al tests of these synthetic compounds for anti-HIV-1 activity was carr ied out using the XTT-based cytopathicity assay (CEM-SS cells) with AZ T as positive control. It was found that the nature of the macrocyclic headgroups affected the anti-HIV-1 activity. Heteroatom containing ma crocyclic headgroups displayed activity in the micromolar range. Metal complexation did not enhance the activity and side-arm substitution r esulted in inactive compounds. Cell viability determined in both Jurka t and CEM-SS cells was strongly dependent on the structure of the macr ocyclic framework. The oxaziridine moieties in the macrocycle were hig hly toxic to CEM-SS and less toxic to Jurkat cell lines, while amide c ontaining macrocycles were toxic to neither.