2-Substituted thiazole-4-carboxamide derivatives as tiazofurin mimics: synthesis and in vitro antitumour activity

Tiazofurin analogues bearing a 5-hydroxymethy1-2-methyl-tetrahydrofuro[2,3-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 1(562 cells might be mediated by apoptosis. It was also found that these analogues induced changes in cell cycle distribution of 1(562 cells. Results of western blot analysis (upregulation of Bax and downregulation of Bc1-2, activation of caspase-3 and the presence of a PARP cleavage product) suggest that tiazofurin mimics (2-4 and 16) in 1(562 cells induced apoptosis in a caspasedependent way. (C) 2014 Elsevier Ltd. All rights reserved.