Abstract
Despite substantial research on cancer therapeutics, systemic toxicity and drug-resistance limits the clinical application of many drugs like cisplatin. Therefore, new chemotherapeutic strategies against different malignancies are needed. Targeted cancer therapy is a new paradigm for cancer therapeutics which targets pathways or chemical entities specific to cancer cells than normal ones. Unlike normal cells, cancer cells contain elevated copper which plays an integral role in angiogenesis. Copper is an important metal ion associated with chromatin DNA, particularly with guanine. Thus, targeting copper via copper-specific chelators in cancer cells can serve as an effective anticancer strategy. New pharmacophore di(2-picolyl)amine (DPA)-3(bromoacetyl) coumarin (ligand-L) was synthesized and characterized by IR, ESI-MS, 1H- and 13C-NMR. Binding ability of ligand-L to DNA/Cu(II) was evaluated using a plethora of biophysical techniques which revealed ligand-L-DNA and ligand-L-Cu(II) interaction. Competitive displacement assay and docking confirmed non-intercalative binding mode of ligand-L with ctDNA. Cyclic voltammetry confirmed ligand-L causes quasi reversible Cu(II)/Cu(I) conversion. Further, acute toxicity studies revealed no toxic effects of ligand-L on mice. To evaluate the chemotherapeutic potential and anticancer mechanism of ligand-L, DNA damage via pBR322 cleavage assay and reactive oxygen species (ROS) generation were studied. Results demonstrate that ligand-L causes DNA cleavage involving ROS generation in the presence of Cu(II). In conclusion, ligand-L causes redox cycling of Cu(II) to generate ROS which leads to oxidative DNA damage and pro-oxidant cancer cell death. These findings will establish ligand-L as a lead molecule to synthesize new molecules with better copper chelating and pro-oxidant properties against different malignancies.
Highlights
DNA is the genetic material which regulates vital processes such as transcription, recombination, proliferation and cell survival
Ligand-L was typically synthesized via a condensation reaction between 3-(2-bromoacetyl)2H-chromen-2-one and di(2-picolyl)amine (DPA) with the elimination of HBr molecule under stirring at room temperature (Fig 1)
A doublet at Δ 7.81 ppm for two protons has been assigned to aromatic H-5 and H-8 protons of coumarin nucleus
Summary
DNA is the genetic material which regulates vital processes such as transcription, recombination, proliferation and cell survival. Targeted anticancer therapy using novel coumarin nucleus-based DPA drug-like molecular entity of extensive research for designing new anticancer agents against different malignancies [1]. DNA cleaving agents have attracted considerable interest in the field of molecular biology and drug development [2]. Metal-containing compounds have been developed with extensive applications in wide ranging fields such as material and biological sciences [3, 4]. The present treatment regiments for chemotherapy under the class of metal-containing compounds such as platinum-based drug (cisplatin) for different malignancies. The major disadvantages of cisplatin (heavy-metal based drug) include various side effects such as severe systemic toxicity (hepatotxicity and nephrotoxicity) and increased drug resistance [5, 6]
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