期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 50, 期 -, 页码 236-254出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.01.058
关键词
Garlic; Ajoene; End-substituted ajoene derivatives; Structure-activity; Vinyl disulfide; Anti-cancer; WHCO1 oesophageal cancer cell-line
资金
- South African Research Chairs Initiative (SARCHI) of the Department of Science and Technology
- National Research Foundation (NRF)
- Medical Research Council (MRC) of South Africa and the University of Cape Town
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 antiproliferation 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 mu M (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. (C) 2012 Elsevier Masson SAS. All rights reserved.
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