Bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment exerting potent antiproliferative activity through microtubule destabilization

Eur J Med Chem. 2018 Sep 5;157:50-61. doi: 10.1016/j.ejmech.2018.07.060. Epub 2018 Jul 29.


Novel bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment as antiproliferative agents by targeting tubulin were synthesized and their preliminary structure activity relationships (SARs) were explored. Among all these chemical agents, 2-(Benzo[d]oxazol-2-ylthio)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)acetamide (4d) exhibited the potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.45 μM by induction of G2/M pahse arrest and cell apoptosis. In addition, 4d could change the membrane potential (ΔΨ) of the mitochondria against MGC-803 cells. Importantly, 4d acted as a novel tubulin polymerization inhibitor binding to colchicine site with an IC50 value of 3.35 μM.

Keywords: 3,4,5-Trimethoxyphenyl fragment; Apoptosis; Colchicine site; G2/M; Tubulin polymerization; ΔΨ.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Microtubules / drug effects*
  • Microtubules / metabolism
  • Models, Molecular
  • Molecular Structure
  • Polymerization / drug effects
  • Structure-Activity Relationship
  • Tubulin / drug effects
  • Tubulin / metabolism


  • Antineoplastic Agents
  • Heterocyclic Compounds
  • Tubulin