DNA binding to guide the development of tetrahydroindeno[1,2-b]pyrido[4,3,2-de]quinoline derivatives as cytotoxic agents

J Med Chem. 2004 Jul 1;47(14):3665-73. doi: 10.1021/jm0400193.

Abstract

The tetrahydroindeno[1,2-b]pyrido[4,3,2-de]quinoline chromophore was initially designed as a DNA intercalating unit because of its planar structure. Unexpectedly, one molecule (15d) bearing two N-methylpiperazine chains on both sides of this condensed pentacyclic skeleton fits into the minor groove of DNA and preferentially recognizes AT-rich sequences. The monosubstituted compound 16d was identified as a potent cytotoxic DNA intercalator, whereas the disubstituted analogue 15d represents a new structural motif for the development of DNA sequence-reading small molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Circular Dichroism
  • DNA / chemistry*
  • DNA Footprinting
  • Drug Screening Assays, Antitumor
  • Fluorometry
  • Humans
  • Intercalating Agents / chemical synthesis
  • Intercalating Agents / chemistry
  • Intercalating Agents / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Structure-Activity Relationship
  • Transition Temperature

Substances

  • 4,5-dimethoxy-10-(3-(4-methyl)piperazin-1-ylpropoxy)-1,2,3,12-tetrahydroindeno(1,2-b)pyrido(4,3,2-de)quinoline
  • 4,5-dimethoxy-3-(2-(4-methyl)piperazin-1-ylacetyl)-10-(3-(4-methyl)piperazin-1-ylpropoxy)-1,2,3,12-tetrahydroindeno(1,2-b)pyrido(4,3,2-de)quinoline
  • Antineoplastic Agents
  • Intercalating Agents
  • Piperazines
  • Quinolines
  • DNA