Design, synthesis, biological evaluation and molecular docking of new 1,3,4-oxadiazole homonucleosides and their double-headed analogs as antitumor agents

Bioorg Chem. 2021 Mar:108:104558. doi: 10.1016/j.bioorg.2020.104558. Epub 2020 Dec 15.

Abstract

A novel series of homonucleosides and their double-headed analogs containing theophylline, 1,3,4-oxadiazole, and variant nucleobases was designed and synthesized. The new derivatives were fully characterized by HRMS, FT-IR, 1H NMR, and 13C NMR. The cytotoxic activities of all prepared compounds were screened in vitro against four cell lines, including fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). The double-headed analogue 18 showed marked growth inhibition against all the cell lines tested, specifically in HT-1080, with an IC50 values of 17.08 ± 0.97 µM. The possible mechanism of apoptosis was investigated using Annexin V staining, caspase-3/7 activity, and analysis cell cycle progression. The compound 18 induced apoptosis through caspase-3/7 activation and cell-cycle arrest in HT-1080 and A-549 cells. The molecular docking confirms that the compound 18 activated caspase-3 via the formation of hydrogen bonds and hydrophobic interactions.

Keywords: 1,3,4-Oxadiazole homonucleosides; Anticancer activity; Double-headed analogs; Molecular docking.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Docking Simulation*
  • Molecular Structure
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry
  • Nucleosides / pharmacology*
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Nucleosides
  • Oxadiazoles
  • 1,3,4-oxadiazole