Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition

J Enzyme Inhib Med Chem. 2020 Dec;35(1):744-758. doi: 10.1080/14756366.2020.1740695.

Abstract

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3-14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC50 range: 5.13-17.95 μM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds 4a and 13 potently inhibited TNF-α (IC50 values: 2.01 and 6.72 μM, respectively) compared with celecoxib (IC50=6.44 μM). Compounds 4b and 13 potently inhibited COX-2 (IC50 values: 1.08 and 1.88 μM, respectively) comparable to that of celecoxib (IC50=0.68 μM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC50 values: 5.62, 5.65, and 3.98 μM, respectively) compared with the reference drug roflumilast (IC50=1.55 μM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.HighlightsAntitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated.The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors.Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition.Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.

Keywords: 2-cyclopentyloxyanisole scaffold; Synthesis; antitumor activity; enzyme inhibition assay; docking study.

MeSH terms

  • Anisoles / chemical synthesis
  • Anisoles / chemistry
  • Anisoles / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / chemical synthesis
  • Cyclooxygenase 2 Inhibitors / chemistry
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Docking Simulation*
  • Molecular Structure
  • Phosphodiesterase 4 Inhibitors / chemical synthesis
  • Phosphodiesterase 4 Inhibitors / chemistry
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors

Substances

  • Anisoles
  • Antineoplastic Agents
  • Cyclooxygenase 2 Inhibitors
  • Phosphodiesterase 4 Inhibitors
  • Tumor Necrosis Factor-alpha
  • anisole
  • Cyclooxygenase 2
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, human

Grants and funding

The authors express their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-163.