Structure-activity studies on the anti-proliferation activity of ajoene analogues in WHCO1 oesophageal cancer cells

Eur J Med Chem. 2012 Apr:50:236-54. doi: 10.1016/j.ejmech.2012.01.058. Epub 2012 Feb 11.

Abstract

The organosulfur compound ajoene derived from the rearrangement of allicin found in crushed garlic can inhibit the proliferation of tumour cells by inducing G(2)/M cell cycle arrest and apoptosis. We report on the application of a concise four-step synthesis (Hunter et al., 2008 [1]) that allows access to ajoene analogues with the end allyl groups substituted. A library of twelve such derivatives tested for their anti-proliferation activity against WHCO1 oesophageal cancer cells has identified a derivative containing p-methoxybenzyl (PMB)-substituted end groups that is twelve times more active than Z-ajoene, with an IC(50) of 2.1μM (Kaschula et al., 2011 [2]). Structure-activity studies involving modification of the sulfoxide and vinyl disulfide groups of this lead have revealed that the disulfide is the ajoene pharmacophore responsible for inhibiting WHCO1 cell growth, inducing G(2)/M cell cycle arrest and apoptosis by caspase-3 activation, and that the vinyl group serves to enhance the anti-proliferation activity a further eightfold. Reaction of the lead with cysteine in refluxing THF as a model reaction for ajoene's mechanism of action based on a thiol/disulfide exchange reveals that the allylic sulfur of the vinyl disulfide is the site of thiol attack in the exchange.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects*
  • Disulfides / chemistry*
  • Disulfides / pharmacology*
  • Esophageal Neoplasms / drug therapy*
  • Flow Cytometry
  • Garlic / chemistry
  • Growth Inhibitors / chemistry
  • Growth Inhibitors / pharmacology
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship
  • Sulfoxides
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Disulfides
  • Growth Inhibitors
  • Sulfoxides
  • ajoene
  • Caspase 3