Design, synthesis, and biological evaluation of novel pyridine-bridged analogues of combretastatin-A4 as anticancer agents

J Med Chem. 2014 Apr 24;57(8):3369-81. doi: 10.1021/jm500002k. Epub 2014 Apr 7.


A series of novel pyridine-bridged analogues of combretastatin-A4 (CA-4) were designed and synthesized. As expected, the 4-atom linker configuration retained little cytotoxicities in the compounds 2e, 3e, 3g, and 4i. Activities of the analogues with 3-atom linker varied widely depending on the phenyl ring substitutions, and the 3-atom linker containing nitrogen represents the more favorable linker structure. Among them, three analogues (4h, 4s, and 4t) potently inhibited cell survival and growth, arrested cell cycle, and blocked angiogenesis and vasculature formation in vivo in ways comparable to CA-4. The superposition of 4h and 4s in the colchicine-binding pocket of tubulin shows the binding posture of CA-4, 4h, and 4s are similar, as confirmed by the competitive binding assay where the ability of the ligands to replace tubulin-bound colchicine was measured. The binding data are consistent with the observed biological activities in antiproliferation and suppression of angiogenesis but are not predictive of their antitubulin polymerization activities.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Bibenzyls / pharmacology*
  • Binding Sites
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Chick Embryo
  • Colchicine / metabolism
  • Drug Design
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Polymerization
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • Tubulin / chemistry
  • Tubulin Modulators / chemical synthesis*
  • Tubulin Modulators / pharmacology


  • Antineoplastic Agents
  • Bibenzyls
  • Pyridines
  • Tubulin
  • Tubulin Modulators
  • combretastatin
  • Colchicine