Antitumour tiazofurin analogues embedded with an amide moiety at the C-2′ position

• Published in: Tetrahedron 2011-09, Vol.67 (36), p.6847-6858
• Main Authors: Popsavin, Mirjana, Svirčev, Miloš, Torović, Ljilja, Bogdanović, Gordana, Kojić, Vesna, Jakimov, Dimitar, Spaić, Saša, Aleksić, Lidija, Popsavin, Velimir
• Format: Article
• Language: English
• Subjects: Analogue; Antineoplastic agents; Antitumour activity; Apoptosis; Biological and medical sciences; Biotechnology; C-nucleosides; Carbohydrates with 4, 5, 6, ... C atoms, dissacharides and oligosaccharides; Carbohydrates. Nucleosides and nucleotides; Chemistry; Exact sciences and technology; General aspects; Human; In vitro testing; Medical sciences; Methyl alcohol; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Pharmacology. Drug treatments; Preparations and properties; Ribofuranosyl-thioamides; Synthesis (chemistry); Tiazofurin; Tumours
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2011.06.090

Synthesis of four new tiazofurin analogues has been accomplished starting from d-glucose. The key step of the synthesis was the three-step cascade that enabled an efficient hydrogen sulfide mediated one-pot conversion of 2-azido-3- O-acyl-ribofuranosyl cyanides to the corresponding 2-alkylamido ribofuranosyl thiocarboxamides. The resulting key intermediates were first converted to protected tiazofurin derivatives by cyclocondensation with ethyl bromopyruvate, and finally to target C-nucleosides by treatment with ammonia in methanol. In vitro cytotoxicities of tiazofurin analogues against a number of human tumour cell lines were recorded and compared with those observed for the parent molecule (tiazofurin), as well as the commercial antitumour agent doxorubicin (DOX). Analogues 2b– d have shown a potent in vitro cytotoxic activity against human myelogenous leukaemia K562. Among solid tumour cell lines, HT29 was sensitive only to 2d, while HeLa cells were sensitive to 2a, 2b and 2d. Only analogue 2a was highly cytotoxic against MCF-7 cells. No tiazofurin analogue exhibits any significant cytotoxicity towards normal foetal lung MRC-5 cells. Downregulation of Bcl-2, activation of caspase-3 and presence of cleavage product of PARP suggest that the cytotoxic effects of tiazofurin analogues 2a– d in K562 might be mediated by apoptosis in a caspase-dependent way. On the contrary, tiazofurin did not induce apoptosis of K562 cells, which suggests a different mechanism of action, most probably through the inhibition of IMPDH. Flow cytometry and Western blot analysis data agreed well with the results of MTT assay, and enabled identification of analogue 2c as the most promising antitumour agent that preferentially target cancer cells over normal cells and thus represents a new lead for further optimization. [Display omitted]