Novel substituted benzothiophene and thienothiophene carboxanilides and quinolones: synthesis, photochemical synthesis, DNA-binding properties, antitumor evaluation and 3D-derived QSAR analysis

J Med Chem. 2012 Jun 14;55(11):5044-60. doi: 10.1021/jm300505h. Epub 2012 Jun 6.

Abstract

A series of new N,N-dimethylaminopropyl- and 2-imidazolinyl-substituted derivatives of benzo[b]thienyl- and thieno[2,3-b]thienylcarboxanilides and benzo[b]thieno[2,3-c]- and thieno[3',2':4,5]thieno[2,3-c]quinolones were prepared. Quinolones were prepared by the reaction of photochemical dehydrohalogenation of corresponding anilides. Carboxanilides and quinolones were tested for the antiproliferative activity. 2-Imidazolinyl-substituted derivatives showed very prominent activity. By use of the experimentally obtained antitumor measurements, 3D-derived QSAR analysis was performed for the set of compounds. Highly predictive 3D-derived QSAR models were obtained, and molecular properties that have the highest impact on antitumor activity were identified. Carboxanilides 6a-c and quinolones 9a-c and 11a were evaluated for DNA binding propensities and topoisomerases I and II inhibition as part of their mechanism of action assessment. The evaluated differences in the mode of action nicely correlate with the results of the 3D-QSAR analysis. Taken together, the results indicate which modifications of the compounds from the series should further improve their anticancer properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / chemical synthesis*
  • Anilides / chemistry
  • Anilides / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • DNA / chemistry*
  • Drug Screening Assays, Antitumor
  • Humans
  • Nucleic Acid Denaturation
  • Photochemical Processes
  • Principal Component Analysis
  • Quantitative Structure-Activity Relationship*
  • Quinolones / chemical synthesis*
  • Quinolones / chemistry
  • Quinolones / pharmacology
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / pharmacology
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology

Substances

  • Anilides
  • Antineoplastic Agents
  • Quinolones
  • Thiophenes
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • DNA