Intercalating, cytotoxic, antitumour activity of 8-chloro and 4-morpholinopyrimido [4',5':4,5]thieno(2,3-b)quinolines.

Circular dichroism, hydrodynamic methods, absorbance and fluorescence titration's were employed to study the interaction of 8-chloropyrimido[4',5':4,5]thieno(2,3-b)quinolin-4(3H)-one (chloro-PTQ) and 4-morpholinopyrimido[4',5':4,5]thieno(2,3-b)quinoline (morpholino-PTQ) with DNA. The association constant of chloro-PTQ and morpholino-PTQ were of the order of 10(5) and 10(6) M(-1). The fluorescence properties at ionic strength of 10mM are best fit by the neighbor exclusion model, with Ki of 0.3 x 10(4) M(-1) to 3.2 x 10(6) M(-1). CD spectra indicate that stacking of these compounds with DNA induces strong helicity in the usually disordered structure of the double strand. Viscosity experiments with sonicated rod like DNA fragments, produced a calculated length of 2.4A/bound of chloro/morpholino-PTQ molecule. The binding of chloro/morpholino-PTQ to DNA increased the melting temperature by about 1.5-7.0 degrees C. The cytotoxicity of these compounds on K-562, HL-60, Colo-205 and B16F10 melanoma are quite similar and IC(50) was in the range of 1.1-8muM. The anticancer efficacy against B16F10 melanoma has provided evidence of major anticancer activity for morpholino-PTQ. Single or multiple i.p. doses of compounds showed high level of activity against the subcutaneous (s.c.) grafted B16 melanoma with a significant increase in life span (161% and 272%). The aim of this study was to analyze the physicochemical properties of the chloro/morpholino-PTQ in an attempt to understand their superior biological activity. This research offers a new intercalation functional group to DNA targeted drug design.