Copper (II)-based halogen-substituted chromone antitumor drug entities: Studying biomolecular interactions with ct-DNA mediated by sigma hole formation and cytotoxicity activity

Bioorg Chem. 2020 Nov:104:104327. doi: 10.1016/j.bioorg.2020.104327. Epub 2020 Sep 30.

Abstract

Copper-based antitumor drug entities 1-3 derived from substituted (F-, Br-, -CH3) 3-formylchromone pharmacophore were synthesized and thoroughly characterized by spectroscopic and single X-ray crystallographic studies. These complexes show structural novelty due to presence of the X-bonds in chromone scaffold which could facilitate higher propensity for nucleic acids via sigma σ-hole interactions. Therefore, structure-activity relationship of 1-3 was studied by performing ct-DNA binding, pBR322 cleavage and cytotoxicity activity to validate their potential to act as chemotherapeutic drug entities. The binding studies of 1-3 with ct- DNA were carried out employing many biophysical techniques and the corroborative results of these experiments showed intercalation mode of binding and the order of binding was found to be 2 > 1 > 3. The structure of drug entities could facilitated strong halogen bonding interaction (in case of 1 &2) and stability of X bond was rationalized by sigma hole region of positive electrostatic potential on the surface of C-X covalent bond, as determined by gas phase B3LYP computational DFT studies. Interestingly, 2 exhibited most avid binding affinity due to presence of Br- electron withdrawing and polarizable group. Further, cleavage studies of 1-3 with pBR322 plasmid DNA were performed which demonstrated significant cleavage activity, the supercoiled form (Form I) of plasmid DNA was converted to nicked form (Form II) with the appearance of linearized form (Form III) in between two, implicating lethal double strand breaks of DNA. 2 showed predominantly higher cleavage activity following the similar trend as observed for binding studies. The cytotoxicity of the complexes 1-3 was evaluated by MTT assay against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines; complex 2 exhibited specific and selective cytotoxicity for the DU-145 cancer cell line with LC50 value of 1.6 μM.

Keywords: Cleavage studies; Copper complexes; Cytotoxic activity; DFT studies; ct-DNA binding studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromones / chemistry
  • Chromones / pharmacology*
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • Copper / chemistry
  • Copper / pharmacology*
  • Crystallography, X-Ray
  • DNA / chemistry*
  • Density Functional Theory
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Halogens / chemistry
  • Halogens / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Particle Size
  • Structure-Activity Relationship
  • Surface Properties

Substances

  • Antineoplastic Agents
  • Chromones
  • Coordination Complexes
  • Halogens
  • Copper
  • DNA
  • calf thymus DNA