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

Jolanta Sochacka; Marcin Pacholczyk; Małgorzata Jeleń; Beata Morak-Młodawska; Krystian Pluta

doi:10.1016/j.saa.2021.120105

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

Spectrochim Acta A Mol Biomol Spectrosc. 2021 Dec 5:262:120105. doi: 10.1016/j.saa.2021.120105. Epub 2021 Jun 27.

Authors

Jolanta Sochacka¹, Marcin Pacholczyk², Małgorzata Jeleń³, Beata Morak-Młodawska³, Krystian Pluta³

Affiliations

¹ Department of General and Inorganic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland. Electronic address: sochacka1@interia.pl.
² Silesian University of Technology, Department of Systems Biology and Engineering, Faculty of Automatic Control, Electronics and Computer Science, Akademicka 16, 44-100 Gliwice, Poland.
³ Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland.

PMID: 34245970
DOI: 10.1016/j.saa.2021.120105

Abstract

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]thiazine possessing tricyclic, tetracyclic and pentacyclic ring system with the additional N,N-dimethylaminopropyl 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 K^b = 6.31 × 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,N-dimethylaminopropyl group. Chemical potential (μ), chemical hardness (ƞ), electronegativity (χ) and the value of electrons transferred from one system to another (ΔN) 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.

Keywords: Azaphenothiazines; DNA interaction; Molecular docking; Partial intercalation; Spectrophotometry.

MeSH terms

Circular Dichroism
DNA*
Molecular Docking Simulation
Phenothiazines*
Spectrometry, Fluorescence
Spectrophotometry, Ultraviolet
Thermodynamics

Substances

Phenothiazines
azaphenothiazine
DNA
calf thymus DNA