Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of N-alkyl-acridones and N,N'-dialkyl-9,9'-biacridylidenes.

Annalisa Masi,Marios G Krokidis,Irini Dousi,Marianna Kokoli,Eleni K Efthimiadou,Kyriakos Papadopoulos,Chryssostomos Chatgilialoglu,Zara Molphy,Smaragda-Maria Argyri,Andrew Kellett

doi:10.3390/biom9050177

Abstract

The anticancer activity of acridone derivatives has attracted increasing interest, therefore, a variety of substituted analogs belonging to this family have been developed and evaluated for their anti-cancer properties. A series of N-alkyl-acridones 1–6 and N,N′-dialkyl-9,9′-biacridylidenes 7–12 with variable alkyl chains were examined for their topoisomerase I activity at neutral and acidic conditions as well as for their binding capacity to calf thymus and possible radical trapping antioxidant activity. It was found that at a neutral pH, topoisomerase I activity of both classes of compounds was similar, while under acidic conditions, enhanced intercalation was observed. N-alkyl-acridone derivatives 1–6 exhibited stronger, dose-dependent, cytotoxic activity against MCF-7 human breast epithelial cancer cells than N,N′-dialkyl-9,9′-biacridylidenes 7–12, revealing that conjugation of the heteroaromatic system plays a significant role on the effective distribution of the compound in the intracellular environment. Cellular investigation of long alkyl derivatives against cell migration exhibited 40–50% wound healing effects and cytoplasm diffusion, while compounds with shorter alkyl chains were accumulated both in the nucleus and cytoplasm. All N,N′-dialkyl-9,9′-biacridylidenes showed unexpected high scavenging activity towards DPPH or ABTS radicals which may be explained by higher stabilization of radical cations by the extended conjugation of heteroaromatic ring system.

Highlights

Acridone derivatives have been applied in clinics as anti-tumor chemotherapeutics since the1970s
ethidium bromide (EtBr) exposure, the intercalation of the planar cationic molecule into a supercoiled plasmid induces complete relaxation of negatively supercoiled (SC) DNA resulting in a slower DNA migration pattern through the agarose medium (0.5 μM)
The present study identified the topoisomerase I unwinding activity, DNA binding properties, and cytotoxic activity against MCF-7 breast cells of a series of N-alkylacridones and N,N0 -dialkyl-9,90 -biacridylidenes substituted with varying alkyl chains

Summary

Introduction

Acridone derivatives have been applied in clinics as anti-tumor chemotherapeutics since the1970s. Acridone derivatives have been applied in clinics as anti-tumor chemotherapeutics since the. The cytotoxicity of acridone and acridine-based compounds arise from their direct binding to DNA and from interactions with specific biological targets [1]. Additional telomerase and protein-kinase inhibitory activity may contribute to cytotoxic effects in cancer treatment [2]. Analogs with a 2,20 -bis-pyridyl group substituted on the acridone scaffold or with a tetracyclic acridone structures, named as zanthacridones, showed broad antitumor activity against numerous cancer cell lines [3]. Derivatives with terminal ammonium substituents at C2 and C7 positions on the acridone moiety showed significant activity against leukemia CCRF-CEM cells along with limited toxic effect against normal cells proliferation [4]

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Conclusion