Synthesis of 2-anilinopyridine dimers as microtubule targeting and apoptosis inducing agents

Bioorg Med Chem. 2014 Dec 15;22(24):6755-67. doi: 10.1016/j.bmc.2014.11.001.

Abstract

A series of 2-anilinopyridine dimers have been synthesized and evaluated for their anticancer potential. Most of the compounds have showed significant growth inhibition of the cell lines tested and compound 4d was most effective amongst the series displaying a GI50 of 0.99 μM specifically against the prostate cancer cell line (DU145). Studies to understand the mechanism of action of 4d indicates that it disrupts microtubule dynamics by inhibiting tubulin polymerization thereby arresting the cell cycle in G2/M phase. Competitive colchicine binding assay suggests that 4d binds into colchicine binding site of the tubulin. Further from some detailed biological studies like mitochondrial membrane potential, caspase-3 assay, DNA fragmentation analysis and Annexin V-FITC assay it is evident that 4d induces apoptosis.Molecular modeling studies provide an insight into the binding modes of 4d with colchicine binding site of tubulin and the data obtained correlates with the antiproliferative activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemistry
  • Apoptosis / drug effects
  • Binding Sites
  • Binding, Competitive
  • Cell Line, Tumor
  • DNA Fragmentation / drug effects
  • Dimerization
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • M Phase Cell Cycle Checkpoints / drug effects
  • Membrane Potential, Mitochondrial / drug effects
  • Microtubules / chemistry
  • Microtubules / metabolism*
  • Molecular Dynamics Simulation
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemical synthesis
  • Niacinamide / chemistry
  • Niacinamide / toxicity
  • Protein Structure, Tertiary
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / toxicity
  • Tubulin Modulators / chemical synthesis*
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / toxicity

Substances

  • 2-(3,5-bis(trifluoromethyl)phenylamino)-N-(2-(4-fluorophenylamino)pyridin-3-yl)nicotinamide
  • Aniline Compounds
  • Pyridines
  • Tubulin Modulators
  • Niacinamide
  • pyridine
  • aniline