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

The organosulfur compound ajoene derived from the rearrangement of allicin found in crushed garlic can inhibit the proliferation of tumour cells by inducing G2/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 IC50 of 2.1 μM (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 G2/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.

Figure optionsDownload as PowerPoint slideHighlights
► A library of ajoene derivatives with different end-groups has been synthesized.
► Compounds have been evaluated against a WHCO1 oesophageal cancer-cell proliferation.
► A lead with PMB end-groups is twelve times more potent than the ajoene parent.
► A comprehensive structure–activity profile for ajoene has been generated.