DNA-binding characterization of a novel anti-tumour benzo[a]phenazine derivative NC-182: spectroscopic and viscometric studies

Abstract

NC-182 is a novel anti-tumour compound having a benzo[a]phenazine ring. Fluorescence, absorption and c.d. spectroscopy, as well as viscometric titrations, were systematically performed to investigate the interaction mode of this drug with DNA and its effect on DNA conformation, based on comparative measurements with distamycin (DNA minor-groove binder) and daunomycin (DNA-base intercalator). NC-182 was found to be a potent intercalator of DNA, especially the B-form DNA, although no specificity was observed against the base-pair. The binding of NC-182 to B-DNA behaves biphasically, depending on the molar ratio (r) of drug to DNA: NC-182 acts to render the B-form structure rigid at relatively low r value and to promote the transformation of B- to non-B forms at high r values. It was also shown that NC-182 promotes the unwinding of Z-form DNA to B-form. Viscometric, u.v. 'melting' and c.d. experiments further showed that (1) the DNA duplex structure is thermally stabilized by intercalation with NC-182 and (2) the intercalation of NC-182 into a poly(dA).2poly(dT) DNA structure thermally stabilizes the triplex structure, resulting in a melting point close to that of the duplex structure; the melting curves of triplex and duplex structures coincide at r > 0.06. These observations make a significant contribution to our understanding of the biological properties of this novel benzo[a]phenazine derivative, a new anti-tumour tumour agent against multidrug-resistant and sensitive tumours.

Synthesis, structure and in vitro anticancer, DNA binding and cleavage activity of palladium (II) complexes based on isatin thiosemicarbazone derivatives

“…The emission intensity increased with increasing CT DNA concentration. These observations imply that these complexes could strongly interact with CT DNA, and indicate an intercalative mode with the base pairs of the DNA helix …”

Phenazine as an Anticancer Agent

“…NC-182 promotes the unwinding of Z-form DNA to B-form and displays potent DNA intercalation activity with nearly the same binding ability as daunomycin, while having no base specificity (Tarui et al 1994). The mode of interaction of NC-182 with DNA depends on the concentration of the drug, where the intercalative and electrostatic bindings are dominant at low and high concentrations of the drug respectively (Tarui et al 1994). The absence of DNA binding specificity of NC-182 led to the development of NC-190, which is a topoisomerase II inhibitor that inhibits in fact the DNA strand-passing activity of DNA topoisomerase II (Yamagishi et al 1996).…”

“…11.7) (Tarui et al 1994;Yamagishi et al 1996). NC-182 promotes the unwinding of Z-form DNA to B-form and displays potent DNA intercalation activity with nearly the same binding ability as daunomycin, while having no base specificity (Tarui et al 1994).…”

“…11.7) (Tarui et al 1994;Yamagishi et al 1996). NC-182 promotes the unwinding of Z-form DNA to B-form and displays potent DNA intercalation activity with nearly the same binding ability as daunomycin, while having no base specificity (Tarui et al 1994). The mode of interaction of NC-182 with DNA depends on the concentration of the drug, where the intercalative and electrostatic bindings are dominant at low and high concentrations of the drug respectively (Tarui et al 1994).…”

Synthesis, crystal structure, DNA binding and cleavage studies of copper(II) complexes with isoxazole Schiff bases

“…Hydrodynamic measurements (i.e., viscosity and sedimentation) sensitive to length changes are the most critical and least ambiguous tests of binding in solution without crystallographic data [61,62]. …”