Benzothiopyranoindole-based antiproliferative agents: synthesis, cytotoxicity, nucleic acids interaction, and topoisomerases inhibition properties.
Basic Information
ID: ALA1152447
Journal: J Med Chem
Title: Benzothiopyranoindole-based antiproliferative agents: synthesis, cytotoxicity, nucleic acids interaction, and topoisomerases inhibition properties.
Authors: Dalla Via L, Magno SM, Gia O, Marini AM, Da Settimo F, Salerno S, La Motta C, Simorini F, Taliani S, Lavecchia A, Di Giovanni C, Brancato G, Barone V, Novellino E.
Abstract: Novel benzo[3',2':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 IC(50) 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.
CiteXplore: 19725581
DOI: 10.1021/jm900627v
Patent ID: ┄