Heteroleptic Copper(I) Complexes of \u201cScorpionate\u201d Bis-pyrazolyl Carboxylate Ligand with Auxiliary Phosphine as Potential Anticancer Agents: An Insight into Cytotoxic Mode

Rais Ahmad Khan,Farukh Arjmand,Mohammad Usman,Khalid Alfarhan,Sartaj Tabassum,Hamad Allohedan,Perumalsamy Balaji,Rajakumar Dhivya,Claudio Pettinari,Mohammad Abdulkader Akbarsha,Ali Alsalme,Fabio Marchetti

doi:10.1038/srep45229

Abstract

New copper(I) complexes [CuCl(PPh3)(L)] (1: L = LA = 4-carboxyphenyl)bis(3,5-dimethylpyrazolyl)methane; (2: L = LB = 3-carboxyphenyl)bis(3,5-dimethylpyrazolyl)methane) were prepared and characterised by elemental analysis and various spectroscopic techniques such as FT-IR, NMR, UV–Vis, and ESI-MS. The molecular structures of complexes 1 and 2 were analyzed by theoretical B3LYP/DFT method. Furthermore, in vitro DNA binding studies were carried out to check the ability of complexes 1 and 2 to interact with native calf thymus DNA (CT-DNA) using absorption titration, fluorescence quenching and circular dichroism, which is indicative of more avid binding of the complex 1. Moreover, DNA mobility assay was also conducted to study the concentration-dependent cleavage pattern of pBR322 DNA by complex 1, and the role of ROS species to have a mechanistic insight on the cleavage pattern, which ascertained substantial roles by both hydrolytic and oxidative pathways. Additionally, we analyzed the potential of the interaction of complex 1 with DNA and enzyme (Topo I and II) with the aid of molecular modeling. Furthermore, cytotoxic activity of complex 1 was tested against HepG2 cancer cell lines. Thus, the potential of the complex 1 is promising though further in vivo investigations may be required before subjecting it to clinical trials.

Highlights

The designing of new potential anticancer drugs with different mechanisms of action for targeting various cancer cells[10,11,12,13]
The mixed-ligand copper(I) complexes were prepared by reacting CuCl in acetonitrile or methanol/acetonitrile solutions with the ligands LA or LB and triphenylphosphine, in the equimolar stoichiometric ratio at room temperature
To obtain further insight into the binding site of the complex 1 with DNA, we studied the mobility in the presence of recognition elements such as methyl green and distamycin, 4′, Figure 10. (a) Electrophoretic pattern of pBR322 DNA (100 ng) with increasing concentration of complex 1 (5–25 μM) after 30 min incubation time in buffer (5 mMTris-HCl/50 mM NaCl, pH = 7.2 at 25 °C). (b) Cleavage pattern of pBR322 plasmid DNA (100 ng) by complex 1 (10 μM) in the presence of reactive oxygen species viz., DMSO (0.4 mM), EtOH (0.4 mM), NaN3 (0.4 mM) and superoxide dismutase (SOD) (10 U), after incubation for 30 min in the buffer

Summary

Introduction

The designing of new potential anticancer drugs with different mechanisms of action for targeting various cancer cells[10,11,12,13]. Various metal complexes capable of binding efficiently to and cleave DNA under physiological environment are regarded as potential chemotherapeutic agents[14,15,16,17,18,19,20,21]. Numerous studies revealed the potential of auranofin to act as potent cytotoxic agent in vitro and in vivo[42,43] These findings prompted several investigations to focus on the anticancer properties and other biological activities of various metal phosphine complexes. A series of Cu(I) mixed-complexes containing sodium bis(1,2,4-triazol1-yl)acetate or sodium bis(3,5-dimethyl-pyrazol-1-yl)acetate ligands, and phosphine co-ligands were tested for their cytotoxic potential against a panel of human carcinoma cell lines[10,27,44]. The complex 1 was tested against HepG2 human hepatocarcinoma cell to find its cytotoxic property

Methods

Results

Conclusion