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

Abstract

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 10 mM are best fit by the neighbor exclusion model, with Ki of 0.3 × 10 4 M −1 to 3.2 × 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 2.4 Å/bound of chloro/morpholino-PTQ molecule. The binding of chloro/morpholino-PTQ to DNA increased the melting temperature by about 1.5–7.0 °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 1.1–8 μM. 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.