Novel benzo[30,20:5,6]thiopyrano[3,2-b]indol-10(11H)-ones 1a-v were synthesized and evaluated for their antiproliferative activity in an in vitro assay of human tumor cell lines (HL-60 and HeLa). Compounds 1e-v, substituted at the 11-position with a basic side chain, showed a significant ability to inhibit cell growth with IC50 values in the low micromolar range. Linear dichroism measurements showed that all 11-dialkylaminoalkyl substituted derivatives 1e-v behave as DNA-intercalating agents. Fluorimetric titrations demonstrated their specificity in binding to A-T rich regions, and molecular modeling studies were performed on the most active derivatives (1e, 1i, 1p) to characterize in detail the complexation mechanism of these benzothiopyranoindoles to DNA. A relaxation assay evidenced a dose-dependent inhibition of topoisomerase II activity that appeared in accordance with the antiproliferative capacity. Finally, for the most cytotoxic derivative, 1e, a topoisomerase II poisoning effect was also demonstrated, along with a weak inhibition of topoisomerase I-mediated relaxation.
Benzothiopyranoindole-Based Antiproliferative Agents: Synthesis, Cytotoxicity, Nucleic Acids Interaction, and Topoisomerases Inhibition Properties.
MARINI, ANNA MARIA;DA SETTIMO PASSETTI, FEDERICO;SALERNO, SILVIA;LA MOTTA, CONCETTINA;SIMORINI, FRANCESCA;TALIANI, SABRINA;
2009-01-01
Abstract
Novel benzo[30,20:5,6]thiopyrano[3,2-b]indol-10(11H)-ones 1a-v were synthesized and evaluated for their antiproliferative activity in an in vitro assay of human tumor cell lines (HL-60 and HeLa). Compounds 1e-v, substituted at the 11-position with a basic side chain, showed a significant ability to inhibit cell growth with IC50 values in the low micromolar range. Linear dichroism measurements showed that all 11-dialkylaminoalkyl substituted derivatives 1e-v behave as DNA-intercalating agents. Fluorimetric titrations demonstrated their specificity in binding to A-T rich regions, and molecular modeling studies were performed on the most active derivatives (1e, 1i, 1p) to characterize in detail the complexation mechanism of these benzothiopyranoindoles to DNA. A relaxation assay evidenced a dose-dependent inhibition of topoisomerase II activity that appeared in accordance with the antiproliferative capacity. Finally, for the most cytotoxic derivative, 1e, a topoisomerase II poisoning effect was also demonstrated, along with a weak inhibition of topoisomerase I-mediated relaxation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
