New benzothiopyranoindoles (5a-l) and pyridothiopyranoindoles (5m-t), featuring different combinations of substituents (H, Cl, OCH3) 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 anti proliferative activity (GI(50) values spanning from 0.31 to 6.93 mu M) 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-OCH3 group. (C) 2019 Elsevier Masson SAS. All rights reserved.
Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases
Milite C.;
2019-01-01
Abstract
New benzothiopyranoindoles (5a-l) and pyridothiopyranoindoles (5m-t), featuring different combinations of substituents (H, Cl, OCH3) 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 anti proliferative activity (GI(50) values spanning from 0.31 to 6.93 mu M) 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-OCH3 group. (C) 2019 Elsevier Masson SAS. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
