Synthesis and characterization of copper(II) norcraugsodine complexes: Their in vitro binding studies with therapeutic targets (ct-DNA/tRNA/BSA), cleavage, and cytotoxicity profile

Amaryllidaceae alkaloid are well known for their myriad pharmacological properties such as Alzheimer's dementia, antimicrobial, and antitumor. The therapeutic potency of this bio-pharmacophore was attributed to the presence of its versatile ring structure and carbon skeleton of alkaloid group. Herein, we have reported the synthesis of Cu(II) norcraugsodine Schiff base complexes 1 and 2 and their characterization by analytical, and spectroscopic methods. The comprehensive biological evaluation was done by carrying out interaction studies with therapeutic intracellular targets, ct-DNA, tRNA and BSA protein using complementary biophysical techniques. The corroborative results of binding experiments revealed that both complexes exhibit high propensity against ct-DNA (4.98 x 10(4) M-1 and 6.19 x 10(4) M-1) as compared to tRNA (2.00 x 10(4) M-1 and 3.21 x 10(4) M-1), attenuating the effect of ligand scaffold on therapeutic potency of drug candidates, and the order of binding was found to be 2 > 1 > SBL. To gain mechanistic insight of inhibition, DNA cleaving ability of complexes was evaluated by gel electrophoretic assay, the complexes were treated in presence of various activator and scavengers. The cleavage was found to be concentration-dependent exhibiting inhibition in presence of pre-hydroxyl radical scavenger (EtOH), implicating that the cleavage was mediated by discernible hydrolytic pathway. The complexes and the ligand SBL were evaluated for the cytotoxicity response against four resistant cancer cell lines, both the complexes showed much enhanced potency as compared to ligand SBL against most of the cell lines, while complex 2 was more active than 1 towards resistant breast cancer cell line MDA-MB-231. All these studies reconfirmed that on complexation with copper, the therapeutic potency was enhanced multifold as compared to free organic Schiff base.