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 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.
Department of Chemistry, Aligarh Muslim University, Aligarh 202002, Uttar Pradesh, India. Electronic address: farukh_arjmand@yahoo.co.in.
Farukh
F
Arjmand
Department of Chemistry, Aligarh Muslim University, Aligarh 202002, Uttar Pradesh, India.
Imtiyaz
I
Yousuf
Laboratoire Chimie des Matériaux, FSO, Université Mohammed I, Oujda 60000, Morocco.
Taibi ben
Tb
Hadda
Institut de Physique de Rennes, UMR 625, Université de Rennes 1, Campus de Beaulieu Bat. 11 A, 263 av. Général Leclerc, 35042 Rennes Cedex, France.
Loic
L
Toupet
D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009268:Nalidixic Acid / Q000737:chemistry; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C000595887:1R,2R-diaminocyclohexane; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D003510:Cyclohexanes; D004268:DNA-Binding Proteins; D009942:Organometallic Compounds; D059005:Topoisomerase II Inhibitors; D009268:Nalidixic Acid; D012313:RNA; D003300:Copper; D004247:DNA; D004250:DNA Topoisomerases, Type II
Molecular docking studies; Nalidixic acid; Topo-II inhibition assay; U2OS cells; pBR322 DNA cleavage