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Design and Synthesis of 4-Substituted Indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine Derivatives with Antitumor Activity


New derivs. of the indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine system, substituted in the 4 position, were designed as novel antitumor agents because of their theor. capability to form stable complexes with DNA fragments. The calcd. free energies of binding were found in the range -12.76 → -39.68 Kcal/mol. The docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs, whereas the side chain lies along the minor groove. Compds., selected on the basis of the docking studies and suitably synthesized, showed antiproliferative activity against each type of tumor cell line investigated, generally in the low micromolar range. The more active derivs. were shown to be I and II, endowed with significant antiproliferative activity against the renal and CNS subpanels, resp. A mechanism of action closely related to the DNA-interacting drugs can be supposed, although, alternative mechanisms, similar to those of the anthracyclines, can also operate.