Synthesis, DNA binding and in vitro antiproliferative activity of purinoquinazoline, pyridopyrimidopurine and pyridopyrimidobenzimidazole derivatives as potential antitumor agents

In the search for new antitumor agents, 8,10-dimethylpurino[7,8-a]quinazoline-5,9, 11(6H,8H,10H)-triones 1, 8,10-dimethylpyrido [2′,3′:4,5]pyrimido[1,2-f]purine-5,9,11 (6H,8H, 10H)-triones 2, and 5,7-dihydro-5-oxopyrido[3′,2′:5,6]pyrimido[1,2-a]benzimidazoles 3, a series of new planar heteropolycyclic compounds, were synthesized. The approach to understanding their structure-activity relationship involved a physico-chemical investigation of the binding process of these molecules to DNA, considered to be an important target for drug action, and an examination of their biological activity. Thermodynamic parameters of the DNA binding process, intrinsic binding constant and exclusion parameter were determined. The mode of interaction was additionally investigated by means of linear flow dichroism studies. Evaluation of the biological activity included cell growth inhibition in human tumoral cell lines and the ability to induce DNA cleavage in the presence of eukaryotic topoisomerase II. Only compounds of the purinoquinazoline series 1, which are able to form a complex with DNA and to inhibit the topoisomerase II, show antiproliferative activity.