Design, synthesis, and DNA-binding of N-alkyl(anilino)quinazoline derivatives

J Med Chem. 2010 Nov 25;53(22):8089-103. doi: 10.1021/jm1009605. Epub 2010 Oct 29.

Abstract

New N-alkylanilinoquinazoline derivatives 5, 12, 20, and 22 have been prepared from 4-chloro-6,7-dimethoxyquinazoline 3, 4-chloro-6,7-methylenedioxyquinazoline 19, and commercially available anilines. Differents classes of compounds substituted by an aryloxygroup (6a-c, 16a,b, and 17a,b), (aminophenyl)ureas (12a,b and 13a-f), anilines (4a-m, 20a,b), N-alkyl(aniline) (5a-m, 21a,b, 22a,d), and N-aminoalkyl(aniline) (22e-g) have been synthesized. These molecules were evaluated for their cytotoxic activities and as potential DNA intercalating agents. We studied the strength and mode of binding to DNA of these molecules by DNA melting temperature measurements, fluorescence emission, and circular dichroism. The results of various spectral and gel electrophoresis techniques obtained with the different compounds, in particular compounds 5g and 22f, revealed significant DNA interaction. These experiments confirm that the N-aminoalkyl(anilino)-6,7-dimethoxyquinazoline nucleus is an efficient pharmacophore to trigger binding to DNA, via an intercalative binding process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Circular Dichroism
  • DNA / chemistry*
  • Drug Screening Assays, Antitumor
  • Fluorescence
  • Humans
  • Intercalating Agents / chemical synthesis*
  • Intercalating Agents / chemistry
  • Intercalating Agents / pharmacology
  • Nucleic Acid Conformation
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / pharmacology
  • Transition Temperature

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • Intercalating Agents
  • Quinazolines
  • Topoisomerase I Inhibitors
  • DNA