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

Bis-naphthalimidopropyl spermidine (BNIPSpd), spermine (BNIPSpm) and oxa-sp ermine (BNIPOSpm) showed high in vitro cytotoxicity against human breast ca ncer 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, s trong stabilisation of calf thymus DNA duplex in the presence of bis-naphth alimidopropyl polyamine derivatives (BNIPSpd, BNIPSpm and BNIPOSpm) was obs erved by LTV spectrophotometric analysis (T-m = 93.3-97 degreesC compared w ith 75 degreesC for calf thymus DNA without drug). Because of their inheren t fluorescence, these compounds were localised preferentially inside the nu cleus as evidenced by their direct observation under the fluorescence micro scope. The results obtained suggest that the cytotoxic activity of the bis- naphthalimidopropyl polyamines may be in part, caused by their effects on D NA. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.