DNA Interaction Studies of Selected Polyamine Conjugates.

Marta Szumilak,Andrzej Stanczak,Malgorzata Strek,Tadeusz Inglot,Anna Merecz,Boleslaw Karwowski

doi:10.3390/ijms17091560

Abstract

The interaction of polyamine conjugates with DNA double helix has been studied. Binding properties were examined by ethidium bromide (EtBr) displacement and DNA unwinding/topoisomerase I/II (Topo I/II) activity assays, as well as dsDNA thermal stability studies and circular dichroism spectroscopy. Genotoxicity of the compounds was estimated by a comet assay. It has been shown that only compound 2a can interact with dsDNA via an intercalative binding mode as it displaced EtBr from the dsDNA-dye complex, with Kapp = 4.26 × 106 M−1; caused an increase in melting temperature; changed the circular dichroism spectrum of dsDNA; converted relaxed plasmid DNA into a supercoiled molecule in the presence of Topo I and reduced the amount of short oligonucleotide fragments in the comet tail. Furthermore, preliminary theoretical study has shown that interaction of the discussed compounds with dsDNA depends on molecule linker length and charge distribution over terminal aromatic chromophores.

Highlights

Due to the biological significance of DNA double helix in cell growth and proliferation, drugs that target DNA and its associated processes e.g., replication, transcription and translation inevitably dominate in chemotherapy regimens [1]
Lots of research projects are aimed at designing new entities capable of selectively interacting with the double stranded DNA of tumor cells [2]
Among DNA recognizing small molecules, intercalators constitute a very important group of potential anticancer drugs [3]. They interact reversibly with DNA double helix by insertion of planar, aromatic chromophore between adjacent base pairs at the intercalation site which leads to topological changes in the double helix

Summary

Introduction

Due to the biological significance of DNA double helix in cell growth and proliferation, drugs that target DNA and its associated processes e.g., replication, transcription and translation inevitably dominate in chemotherapy regimens [1]. Among DNA recognizing small molecules, intercalators constitute a very important group of potential anticancer drugs [3]. They interact reversibly with DNA double helix by insertion of planar, aromatic chromophore between adjacent base pairs at the intercalation site which leads to topological changes in the double helix (unwinding, lengthening). Representative monointercalators with antitumor activity e.g., doxorubicin, are still valuable drugs Their therapeutic efficacy is often diminished by lack of selectivity, resulting in severe adverse reactions as well as the development of drug resistance [5]. They have unique structural features characterized by the presence of two planar polyaromatic or heteroaromatic systems joined by linker chains of different length and rigidity [7,8,9]

Methods

Findings

Discussion

Conclusion