Interaction of new tri-, tetra-, and pentacyclic azaphenothiazine derivatives with calf thymus DNA: Spectroscopic and molecular docking studies

Azaphenothiazines (AZA), modified phenothiazine derivatives, have been reported to exhibit a wide spectrum of biological activities, including anticancer activities, but the mechanisms of their interactions with biomolecules are not fully recognized. In this work, the mode of interaction of selected AZA with calf thymus DNA was investigated using UV-Vis absorption, fluorescence spectroscopy (competition experiment with ethidium bromide, quenching of fluorescence) and molecular docking. The investigated AZA represent dipyrido[3,4-b;3'4'-e][1,4]thiazine, quino[3,2-b]benzo[1,4]thiazine and diquino[3,2-b;2',3'-e][1,4]t hiazine possessing tricyclic, tetracyclic and pentacyclic ring system with the additional N,Ndimethylaminopropyl group at the nitrogen atom in the 1,4 thiazine ring. The results obtained from spectroscopic studies showed that AZA bind to DNA by insertion of a fragment of the fused rings system between the base pair stack in the double helix of DNA. In addition, the number of rings in the AZA structures seemed to be related to the strength of the interaction, because pentacyclic AZA (binding constant Kb = 6.31 x 106 L/mol) demonstrated 10-fold higher affinity towards DNA than the tetracyclic AZA and about 100-fold higher affinity than that of tricyclic AZA. The molecular docking results showed that the binding mode of AZA to DNA helix was an intercalation mode with the partial insertion of one planar part of the AZA structure (the pyridine or quinoline ring) into the neighboring bases of one of the DNA chains with additional hydrogen bonding with the minor groove through the positively charged N,Ndimethylaminopropyl group. Chemical potential (l), chemical hardness (n), electronegativity (v) and the value of electrons transferred from one system to another (DN) calculated from the HOMO and LUMO energies by the density functional theory method indicated that AZA acted as the electron acceptors to the DNA bases. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

In this study, the interaction mode of selected azaphenothiazines (AZA) with calf thymus DNA was investigated using UV-Vis absorption, fluorescence spectroscopy, and molecular docking. The results showed that AZA bind to DNA by inserting a fragment of the fused rings system between the base pair stack in the double helix. The number of rings in the AZA structures seemed to be correlated with the strength of the interaction, with pentacyclic AZA demonstrating higher affinity towards DNA.