Synthesis and biological activities of bisnaphthalimido polyamines derivatives

A M Dance, Lynda Denise Ralton, Z Fuller, Lesley Milne, Susan Joyce Duthie, Charles Bestwick, Paul Kong Thoo Lin

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

New bisoxynaphthalimidopolyamines (BNIPOPut, BNIPOSpd and BNIPOSpm) were synthesized. Their cytotoxic properties were evaluated against breast cancer MCF 7 cells and compared with bisnaphthalimidopolyamines BNIPSpd and BNIPSpm. Among the bisoxynaphthalimido polyamines, BNIPOSpm and BNIPOSpd exhibited cytotoxic activity with an IC50 of 29.55 and 27.22 muM, respectively, while BNIPOPut failed to exert significant cytotoxicity after 48-h drug exposure. DNA binding was determined by midpoint of thermal denaturation (T-m) measurement, ethidium bromide displacement and DNA gel mobility. Both BNIPOSpm and BNIPOSpd exhibited strong binding affinities with DNA. BNIPOPut had the least effect. The results were compared with other cytotoxic bisnaphthalimido compounds (BNIPSpm and BNIPSpd) previously reported by us. Using the single cell gel electrophoresis assay, it was found that BNIPSpm and BNIPSpd caused substantial DNA damage to MCF 7 treated cells while BNIPOSpm showed no significant effect over a range of drug concentrations after 4-h drug exposure. However, after 12-h drug exposure, BNIPOSpm had induced significant DNA damage similar to that of BNIPSpm (after 4-h drug exposure). Fluorescence microscopic analysis revealed that at 1 muM drug concentration and after 6-h drug exposure, both BNIPSpm and BNIPSpd were located within the cell while the presence of BNIPOSpm, was not observed. Therefore, we conclude that BNIPSpd, BNIPSpm and BNIPOSpm induce DNA damage consistent with their rate of uptake into the cells. (C) 2004 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)19-27
Number of pages9
JournalBiochemical Pharmacology
Volume69
Issue number1
Early online date17 Nov 2004
DOIs
Publication statusPublished - 1 Jan 2005

Keywords

  • bisnaphthalimides
  • synthesis
  • cytotoxicity
  • DNA binding and damage
  • single cell gel electrophoresis assay
  • fluorescence microscopy
  • LU-79553
  • complex

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