Cytotoxicity, DNA binding and localisation of novel bis-naphthalimidopropyl polyamine derivatives

Bis-naphthalimidopropyl spermidine (BNIPSpd), spermine (BNIPSpm) and oxa-spermine (BNIPOSpm) showed high in vitro cytotoxicity against human breast cancer MCF-7 cells with IC50 values of 1.38, 2.91 and 8.45 muM, respectively. These compounds were found to effectively displace the intercalating agent ethidium bromide bound to the calf thymus DNA using fluorimetric methods (C-50 0.08-0.12 muM) and their apparent equilibrium binding constants (K-app) were calculated to be in the range of 10.5-18 x 10(7) M-1. Furthermore, strong stabilisation of calf thymus DNA duplex in the presence of bis-naphthalimidopropyl polyamine derivatives (BNIPSpd, BNIPSpm and BNIPOSpm) was observed by LTV spectrophotometric analysis (T-m = 93.3-97 degreesC compared with 75 degreesC for calf thymus DNA without drug). Because of their inherent fluorescence, these compounds were localised preferentially inside the nucleus as evidenced by their direct observation under the fluorescence microscope. The results obtained suggest that the cytotoxic activity of the bis-naphthalimidopropyl polyamines may be in part, caused by their effects on DNA. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.