Structure–activity studies on the anti-proliferation activity of ajoene analogues in WHCO1 oesophageal cancer cells
| Autor: | Philip Richards, Ellen Ngarande, Roger Hunter, Kani Zilbeyaz, Thozama Ogunleye, Jonathan Cotton, Yabing Wang, Vuyolwethu Siyo, Catherine H. Kaschula, Mino R. Caira, Nashia Stellenboom, Susan Winks, M. Iqbal Parker |
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| Přispěvatelé: | Belirlenecek, Hunter, Roger -- 0000-0001-8775-083X |
| Rok vydání: | 2012 |
| Předmět: |
Allylic rearrangement
Esophageal Neoplasms Stereochemistry Antineoplastic Agents Apoptosis Structure-Activity Relationship chemistry.chemical_compound Ajoene Drug Discovery Tumor Cells Cultured medicine Humans Disulfides Garlic Cell Proliferation Pharmacology chemistry.chemical_classification Molecular Structure Allicin Anti-cancer Caspase 3 Organic Chemistry Structure-activity End-substituted ajoene derivatives Sulfoxide WHCO1 oesophageal cancer cell-line Cell Cycle Checkpoints General Medicine Flow Cytometry Growth Inhibitors chemistry Mechanism of action Sulfoxides Thiol Vinyl disulfide medicine.symptom Organosulfur compounds Cysteine |
| Zdroj: | European Journal of Medicinal Chemistry. 50:236-254 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2012.01.058 |
| Popis: | 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. 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 This work was supported by the South African Research Chairs Initiative (SARCHI) of the Department of Science and Technology, the National Research Foundation (NRF), and research grants from the Medical Research Council (MRC) of South Africa and the University of Cape Town. We thank Roche for the loan of the RTCA SP xCelligence system. We thank Mr Ronnie Dreyer for his assistance with the Flow Cytometry. |
| Databáze: | OpenAIRE |
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