Click and Cut: a click chemistry approach to developing oxidative DNA damaging agents.

Natasha Mcstay,Creina Slator,Fredrik Westerlund,Andrew Kellett,Alex Gibney,Vandana Singh

doi:10.1093/nar/gkab817

Natasha Mcstay, Creina Slator + Show 4 more

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https://doi.org/10.1093/nar/gkab817

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Abstract

Metallodrugs provide important first-line treatment against various forms of human cancer. To overcome chemotherapeutic resistance and widen treatment possibilities, new agents with improved or alternative modes of action are highly sought after. Here, we present a click chemistry strategy for developing DNA damaging metallodrugs. The approach involves the development of a series of polyamine ligands where three primary, secondary or tertiary alkyne-amines were selected and ‘clicked’ using the copper-catalysed azide-alkyne cycloaddition reaction to a 1,3,5-azide mesitylene core to produce a family of compounds we call the ‘Tri-Click’ (TC) series. From the isolated library, one dominant ligand (TC1) emerged as a high-affinity copper(II) binding agent with potent DNA recognition and damaging properties. Using a range of in vitro biophysical and molecular techniques—including free radical scavengers, spin trapping antioxidants and base excision repair (BER) enzymes—the oxidative DNA damaging mechanism of copper-bound TC1 was elucidated. This activity was then compared to intracellular results obtained from peripheral blood mononuclear cells exposed to Cu(II)–TC1 where use of BER enzymes and fluorescently modified dNTPs enabled the characterisation and quantification of genomic DNA lesions produced by the complex. The approach can serve as a new avenue for the design of DNA damaging agents with unique activity profiles.

Highlights

Nucleic acids are ubiquitous biomolecules responsible for mediating faithful cellular replication and translation in most forms of cellular life
This reaction proceeded at room temperature with the product (TCiPrOH, Figure 1C) precipitating in reasonable yield
We identified a click chemistry-based strategy to produce bioactive polynuclear complexes

Summary

Introduction

Nucleic acids are ubiquitous biomolecules responsible for mediating faithful cellular replication and translation in most forms of cellular life Both DNA and RNA are subjected to intensive drug discovery efforts so that cancer, monogenetic, and pathogenic diseases can be effectively treated [1]. Since double helical DNA encodes genetic information, it serves as a primary target for small molecule binding agents [2] These interactions typically involve molecular recognition such as the curvature of the major or minor groove, the negatively charged phosphate backbone, or the space between specific base pairs (steps) required for intercalation. Several important classes of DNA damaging drugs including metallobleomycin and neocarzinostatin are potent non-covalent binding agents In their subsequent oxidative DNA damaging phases they activate C–H deoxyribose bonds producing double stand breaks that covalently modify the underlying nucleic acid structure [6]

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