Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases

Abstract New benzothiopyranoindoles ( 5a-l ) and pyridothiopyranoindoles ( 5m-t ), featuring different combinations of substituents (H, Cl, OCH 3 ) at R 2 -R 4 positions and protonatable R 1 -dialkylaminoalkyl chains, were synthesized and biologically assayed on three human tumor cell lines, showing significant antiproliferative activity (GI 50 values spanning from 0.31 to 6.93 μM) and pro-apoptotic effect. Linear flow dichroism experiments indicate the ability of both chromophores to form a molecular complex with DNA, following an intercalative mode of binding. All compounds displayed a moderate ability to inhibit the relaxation activity of both topoisomerases I and II, reasonably correlated to their intercalative capacities. Cleavable assay performed with topoisomerase I revealed a significant poisoning effect for compounds 5g , 5h , 5s , and 5t . A theoretical model provided by hydrated docking calculations clarified the role of the R 1 -R 4 substituents on the topoisomerase I poison activity, revealing a crucial role of the R 2 -OCH 3 group.