Benzothiopyranoindole-Based Antiproliferative Agents: Synthesis, Cytotoxicity, Nucleic Acids Interaction, and Topoisomerases Inhibition Properties

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-09, Vol.52 (17), p.5429-5441
Main Authors: Dalla Via, Lisa, Marciani Magno, Sebastiano, Gia, Ornella, Marini, Anna Maria, Da Settimo, Federico, Salerno, Silvia, La Motta, Concettina, Simorini, Francesca, Taliani, Sabrina, Lavecchia, Antonio, Di Giovanni, Carmen, Brancato, Giuseppe, Barone, Vincenzo, Novellino, Ettore
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Cell Proliferation - drug effects
DNA - chemistry
DNA - metabolism
DNA Topoisomerases, Type I - chemistry
DNA Topoisomerases, Type II - chemistry
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - toxicity
Fluorometry
General aspects
HeLa Cells
HL-60 Cells
Humans
Indoles - chemical synthesis
Indoles - metabolism
Indoles - pharmacology
Indoles - toxicity
Inhibitory Concentration 50
Medical sciences
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Quantum Theory
Thermodynamics
Titrimetry
Topoisomerase I Inhibitors
Topoisomerase II Inhibitors
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Summary: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 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900627v