Arylamine Analogs of Methylene Blue: Substituent Effect on Aggregation Behavior and DNA Binding.

Alena Khadieva,Olga Mostovaya,Denis Grishaev,Ivan Stoikov,Valeriy Kalinin,Pavel Padnya,Dmitrii Tumakov

doi:10.3390/ijms22115847

Alena Khadieva, Olga Mostovaya + Show 5 more

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https://doi.org/10.3390/ijms22115847

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Abstract

The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new generation of agents for photodynamic therapy. In this study, two new derivatives of phenothiazine, i.e., 3,7-bis(4-aminophenylamino)phenothiazin-5-ium chloride dihydrochloride (PTZ1) and 3,7-bis(4-sulfophenylamino)phenothiazin-5-ium chloride (PTZ2), are synthesized for the first time and characterized by NMR, IR spectroscopy, HRMS and elemental analysis. The interaction of the obtained compounds PTZ1 and PTZ2 with salmon sperm DNA is investigated. It is shown by UV-Vis spectroscopy and DFT calculations that substituents in arylamine fragments play a crucial role in dimer formation and interaction with DNA. In the case of PTZ1, two amine groups promote H-aggregate formation and DNA interactions through groove binding and intercalation. In the case of PTZ2, sulfanilic acid fragments prevent any dimer formation and DNA binding due to electrostatic repulsion. DNA interaction mechanisms are studied and confirmed by UV-vis and fluorescence spectroscopy in comparison with Methylene Blue. The obtained results open significant opportunities for the development of new drugs and photodynamic agents.

Highlights

The study of drug-DNA interactions plays a key role in pharmacology, since small molecules capable of binding genomic DNA can become effective anti-cancer, antibiotic and antiviral therapeutic agents [1]
The main approaches to the introduction of arylamine fragments into the structure of phenothiazine are the Buchwald-Hartwig reaction [18,27,28] and the oxidation of phenothiazine to phenothiazin-5-ium cation followed by nucleophilic addition of aromatic amines (Scheme 1) [17,21,25,29]
Two new 3,7-bis(aryl-amino)phenothiazine derivatives containing two primary amine or two sulfo groups were synthesized. It was shown by UV-Vis fluorescence spectroscopy that substituents in the arylamine fragment play a crucial role in aggregation properties and interaction with DNA

Summary

Introduction

The study of drug-DNA interactions plays a key role in pharmacology, since small molecules capable of binding genomic DNA can become effective anti-cancer, antibiotic and antiviral therapeutic agents [1]. Positively charged molecule fragments can bind to negatively charged DNA phosphate groups through electrostatic interactions. This type of interaction usually occurs on the outer side of the helix. Drug molecules can bind to nucleic acid bases in the major and/or minor groove of the DNA helix through hydrogen bonds and van der Waals interactions. Which is π-stacking between nucleobases and molecule aromatic fragments In this case, a flat heteroaromatic fragment is located between DNA base pairs, and binds perpendicularly to the helix axis. Studying the interactions of intercalative small molecules with DNA opens a significant opportunity in higher generation diagnostic probes and DNA-directed therapeutics design [4]

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