Repurposing the antihistamine drug bilastine as an anti-cancer metallic drug entity: synthesis and single-crystal X-ray structure analysis of metal-based bilastine and phen [Co(II), Cu(II) and Zn(II)] tailored anticancer chemotherapeutic agents against resistant cancer cells

Dalton Trans. 2024 Jun 17;53(24):10126-10141. doi: 10.1039/d4dt00426d.

Abstract

Bilastine (BLA), 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazole-2-yl)-piperidin-1-yl)-ethyl)-phenyl)-2-methylpropanoic acid, is an active antihistamine drug. With the idea of repurposing drugs from the existing pool of 'active' pharmaceutical ingredients, the therapeutic potency of bilastine as an anticancer agent was investigated via the tailored synthesis of a metal-based anticancer drug formulation of the type [BLA(phen)2M(II)]+·X-, where M = Co, Cu, and Zn and X- = NO3 and ClO4. The synthesized metal-based chemotherapeutics derived from the bilastine drug that acts as a ligand were thoroughly characterized using spectroscopic techniques, namely, UV-vis, FT-IR, and EPR (in the case of 1 and 2); 1H-NMR and 13C-NMR (in the case of 3); ESI-MS and single-crystal X-ray diffraction studies. Comprehensive biological studies (DNA binding, cleavage, and cytotoxic activity) using various biophysical and gel electrophoretic methods were carried out to validate their potential as anticancer agents. The cytotoxic activity of 'therapeutically promising' copper(II)-based drug candidate 2 was evaluated against MCF-7, MBA-MD-231, HeLa, HepG2, and Mia-PaCa-2 cancer cells via an SRB assay, and the results demonstrated 2 as a potent anticancer agent at low nanomolar concentrations against all tested cancer cells, preferably with a much superior anticancer efficacy against human pancreatic cancer cells.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cobalt* / chemistry
  • Cobalt* / pharmacology
  • Coordination Complexes* / chemical synthesis
  • Coordination Complexes* / chemistry
  • Coordination Complexes* / pharmacology
  • Copper* / chemistry
  • Copper* / pharmacology
  • Crystallography, X-Ray
  • Drug Repositioning*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Histamine Antagonists / chemical synthesis
  • Histamine Antagonists / chemistry
  • Histamine Antagonists / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Zinc* / chemistry
  • Zinc* / pharmacology

Substances

  • Antineoplastic Agents
  • Copper
  • Zinc
  • Coordination Complexes
  • Cobalt
  • Benzimidazoles
  • Piperidines
  • Histamine Antagonists