Synthesis, characterization and anticancer evaluation of nitrogen-substituted 1-(3-aminoprop-1-ynyl)-4-hydroxyanthraquinone derivatives

Nafisa S Sirazhetdinova,Dmitry S Baev,Victor A Savelyev,Jamsranjav Ganbaatar,Tatyana G Tolstikova,Elvira E Shults,Tatyana S Golubeva,Lyubov S Klimenko

doi:10.1007/s00044-021-02754-1

Abstract

Anthraquinones are of significant interest due to their biological activity, coloring properties, and synthetic applications. Here, we describe a mild and convenient method for modification of 1-ethynyl-4-hydroxyanthraquinone that was obtained from the Sonogashira cross-coupling reaction of 1-hydroxy-4-iodoanthraquinone with alkynes. The copper(I) catalyzed one-pot three-component reaction (A3-coupling) of the new 1-ethynyl-4-hydroxyanthraquinone with secondary amines and formaldehyde was the main approach for the synthesis of nitrogen-substituted 1-[3-(amino)prop-1-ynyl]-4-hydroxyanthraquinones. The influence of different substituents in the amine on reaction rate and yield has been evaluated. The cytotoxicity of 1-ethynyl-4-hydroxyanthraquinones was assessed using the conventional MTT assay. Among all compounds synthesized, anthraquinone-propargylamine derivatives 28, 29, 30, and 34 possess the most promising cytotoxic potential towards glioblastoma cancer cells; compounds 14 and 19 shown selectivity towards the prostate cancer cells DU-145, and 18, 24 — on breast cancer cell line MCF-7. The grown inhibition on these cancer cells by compounds 18 and 24 was comparable to those of standard drug Doxorubicin. Molecular modeling of new anthraquinone derivatives in DNA G-quadruplex binding sites was performed to help understand the observed SAR trends.

Highlights

The derivatives of anthracene-9,10-dione were of interest in many applications, in particular, are well known for their diverse and profound biological activities [1]
Taken into account the interest to substituted anthraquinones as anticancer agents we evaluated the cytotoxicity of the synthesized compounds toward cancer cell lines in vitro
We found that the reaction of compound 12, formaldehyde and diethylamine 13 in dioxane in the presence of 0.02 equiv of copper(I) iodide at 65oC procceds smoothly, and after 30 min the alkyne was almost consumed and the desired N-(dimethyl)- substituted 1-(3-aminopropargyl)-4-hydroxyanthraquinone 14 was isolated in the yield 50% (Scheme 2)

Summary

Introduction

The derivatives of anthracene-9,10-dione (anthraquinone) were of interest in many applications, in particular, are well known for their diverse and profound biological activities [1].

Results

Conclusion