Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases

Eur J Med Chem. 2019 Mar 1:165:46-58. doi: 10.1016/j.ejmech.2019.01.015. Epub 2019 Jan 9.

Abstract

New benzothiopyranoindoles (5a-l) and pyridothiopyranoindoles (5m-t), featuring different combinations of substituents (H, Cl, OCH3) at R2-R4 positions and protonatable R1-dialkylaminoalkyl chains, were synthesized and biologically assayed on three human tumor cell lines, showing significant antiproliferative activity (GI50 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 R1-R4 substituents on the topoisomerase I poison activity, revealing a crucial role of the R2-OCH3 group.

Keywords: Antiproliferative activity; Benzothiopyranoindoles; Pyridothiopyranoindoles; Topoisomerase I poisons; Topoisomerases.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA / metabolism
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Molecular Docking Simulation
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry*
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry*

Substances

  • Antineoplastic Agents
  • Indoles
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • DNA