Rational Design of a Cytotoxic Dinuclear Cu₂ Complex That Binds by Molecular Recognition at Two Neighboring Phosphates of the DNA Backbone

Abstract

The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6-7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu(II)2 complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV-vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu(II)2 complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells.

Synthesis, characterization, DNA binding, apoptosis and molecular docking of three Mn(II), Zn(II) and Cu(II) complexes with terpyridine‐based carboxylic acid

“…The Zn(II) complex has DNA binding ability stronger than that of the corresponding Cu(II) analogue, which is expected due to the z* effect and geometry . Variation of the metal ions may allow a fine tuning of the kinetic and thermodynamic stability so that potentially a new family of DNA‐binding molecules evolves that can be cytotoxic to cancer cells . According, we make the following suggestions: (1) the reactions of the three complexes between adjacent DNA base pairs have taken place in an intercalative manner and (2) plots of the quenching of fluorescence of EtBr–DNA by successive addition of 1 , 2 and 3 give linear Stern–Volmer equations with K sq values indicating stronger interaction of 2 with DNA than 1 and 3 .…”

Copper as the Target for Anticancer Nanomedicine

“…[98][99][100][101][102] Numerous copper complexes have been tested as DNA-targeting agents. [98][99][100][101][102] Numerous copper complexes have been tested as DNA-targeting agents.…”

Syntheses, crystal structures and in vitro anticancer activities of oxovanadium(IV) complexes of amino acid Schiff base and 1,10-phenanthroline ligands

“…Cisplatin was the first platinum-based complex to be used as an effective anticancer drug [1,2]. Cisplatin and related Pt(II) complexes exhibit remarkable anticancer activities; however, they suffer from problems related to severe side effects in normal tissue, nephrotoxicity, drug resistance and cost per patient.…”