2-Substituted thiazole-4-carboxamide derivatives as tiazofurin mimics: synthesis and in vitro antitumour activity |
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Authors: | Mirjana Popsavin Vesna Koji? Saša Spai? Miloš Svir?ev Gordana Bogdanovi? Dimitar Jakimov Lidija Aleksi? Velimir Popsavin |
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Institution: | 1. Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovi?a 3, 21000 Novi Sad, Serbia;2. Oncology Institute of Vojvodina, Put doktora Goldmana 4, 21204 Sremska Kamenica, Serbia |
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Abstract: | Tiazofurin analogues bearing a 5-hydroxymethyl-2-methyl-tetrahydrofuro2,3-d]1,3]dioxol-6-ol moiety as a sugar mimic (2 and 3), and two novel thiazole-based acyclo-C-nucleosides 4 and 16 have been synthesized in multistep sequences starting from d-xylose (compounds 2 and 3) or from d-arabinose (compounds 4 and 16). All synthesized analogues showed potent in vitro antitumour activities against a panel of human tumour cell lines. Flow cytometry data suggest that cytotoxic effects of analogues 2–4 and 16 in the culture of K562 cells might be mediated by apoptosis. It was also found that these analogues induced changes in cell cycle distribution of K562 cells. Results of western blot analysis (upregulation of Bax and downregulation of Bcl-2, activation of caspase-3 and the presence of a PARP cleavage product) suggest that tiazofurin mimics (2–4 and 16) in K562 cells induced apoptosis in a caspase-dependent way. |
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Keywords: | Tiazofurin Thiazole-4-carboxamide Analogue synthesis Antitumour activity Apoptosis |
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