New modulated design and synthesis of quercetin–CuII/ZnII–Sn2IV scaffold as anticancer agents: in vitro DNA binding profile, DNA cleavage pathway and Topo-I activity

Abstract

New molecular topologies quercetin-Cu(II)-Sn2(IV) and Zn(II)-Sn2(IV)1 and 2 were designed and synthesized to act as potential cancer chemotherapeutic agents. Their interaction with CT DNA by UV-vis and fluorescence spectroscopy was evaluated revealing an electrostatic mode of binding. Quercetin complexes are capable of promoting DNA cleavage involving both single and double strand breaks. Complex 1 cleaved pBR322 DNA via an oxidative mechanism while 2 followed a hydrolytic pathway, accessible to the minor groove of the DNA double helix in accordance with molecular docking studies with the DNA duplex of sequence d(CGCGAATTCGCG)2 dodecamer demonstrating that the complex was stabilized by additional electrostatic and hydrogen bonding interactions with the DNA. ROS such as OH˙, H2O2 and O2˙(-) are the major metabolites responsible for chronic diseases such as cancer, respiratory disorders, HIV, and diabetes etc., therefore eliminating ROS by molecular scaffolds involving SOD enzymatic activity has emerged as a potential way to develop a novel class of drugs. Therefore, in vitro superoxide dismutase activity of redox active complex 1 was evaluated by using a xanthine/xanthine oxidase-NBT assay which showed an IC50 value of 2.26 μM. Moreover, the cytotoxicity of both the complexes were screened on a panel of human carcinoma cell lines (GI50 values <8.7 μM) which revealed that 1 has a better prospect of acting as a cancer chemotherapeutic agent, and to elucidate the mechanism of tumor inhibition, Topo-I enzymatic activity was carried out. Furthermore, molecular modeling studies were carried out to understand molecular features important for drug-enzyme interactions which offer new insights into the experimental model observations.

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

“…DNA binding experiments that included spectral absorption studies, and fluorescence, conformed to the standard methods505481 and practices previously adopted by our laboratory8283. Standard error limits were estimated using all data points.…”

Nuclear blebbing of biologically active organoselenium compound towards human cervical cancer cell (HeLa): In vitro DNA/HSA binding, cleavage and cell imaging studies

“…Competitive binding of drugs to DNA with EB could provide rich information with regard to the DNA binding affinity [23]. The EB fluorescence intensity will be enhanced in the presence of DNA because of its intercalation into the helix, and it is quenched by the addition of another molecule either by replacing the EB [24]. The extent of reduction of the emission intensity gives a measure of the binding propensity of the compounds to CT-DNA.…”

“…If one strand is cleaved, the SC DNA produces a slower-moving nicked circular (NC) form. If both strands are cleaved, the linear (L) form is generated which migrates in between the SC and NC forms [34]. To further confirm the hydrolytic pathway mediated by compound 1, DNA religation experiment was performed in which supercoiled pBR322 DNA was treated with T4 ligase enzyme and subjected to gel electrophoresis.…”

Synthesis and structure elucidation of a copper(II) Schiff-base complex: In vitro DNA binding, pBR322 plasmid cleavage and HSA binding studies

“…DNA is a primary intracellular target of anti-cancer drugs because it regulates many biochemical processes that occur in the cellular system, many small molecules exert their anticancer activities by binding with DNA, thereby altering DNA replication, blocking the division of cancer cells and resulting in the cell death [1][2][3]. The different loci present in the DNA are involved in various regulatory processes such as gene expression, gene transcription, mutagenesis and carcinogenesis [4].…”