Synthesis, crystal structure and antiproliferative activity of Cu(II) nalidixic acid-DACH conjugate: Comparative in vitro DNA/RNA binding profile, cleavage activity and molecular docking studies

Nalidixic acid-DACH conjugate Cu(II) molecular entity, 1 was synthesized, thoroughly characterized by spectroscopic techniques (FT-IR, EPR and ESI-MS) and single crystal X-ray diffraction technique as a potential chemotherapeutic drug candidate for cancer oncology. Complex 1 was found to be a potent drug-like molecular entity in confirmation with Lipinski rules. 1R,2R-diaminocyclohexane (DACH) ligand scaffold (which reduces the drawbacks of cisplatin analogues) and nalidixic acid pharmacophore make it a suitable drug entity targeting nucleic acids. To evaluate the chemotherapeutic potential of 1 comparative in vitro DNA/RNA interaction studies have been investigated by employing various biophysical techniques (UV-vis, fluorescence, circular dichorism, viscosity, cyclic voltammetry and FT-IR), cleavage activity and Topo-II inhibition assay. Further, mechanistic investigation revealed the efficiency of I to cleave pBR322 DNA strands by an oxidative pathway involving the generation of ROS and preferential selectivity towards the A-T region of DNA major groove. Antiproliferative activity in conjugation with flow cytometry analysis of 1 against human osteoblastoma cell line (U2OS) suggested a cell cycle arrest at S phase. This work further advances our knowledge for the development and design of small RNA targeted therapeutic molecules which are under exploited drug targets. (C) 2014 Elsevier Masson SAS. All rights reserved.