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

摘要

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,2K-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 1 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.