Synthesis and antiproliferative activity of new pseudo-C-nucleosides with pyrazole and tetrazole aglycons and a functionalized xylofuranose scaffold.

New pseudo-C-nucleosides with pyrazole or tetrazole aglycones, bearing [3.3.0]furofuranone or [3.3.0]furodioxole rings as sugar mimics, were synthesised through a multistep sequence starting from d-glucose. The key step in the synthesis of pyrazole derivatives was the 1,3-dipolar cycloaddition of unsaturated esters 9 and 10 with diazomethane, yielding 2-pyrazoline 11 as a mixture of stereoisomers. Treatment of 11 with a solution of chlorine in carbon tetrachloride yields the pyrazole 12, which is subsequently converted to the pseudo-C-nucleoside 13 after treatment with saturated ammonia in methanol. Esterification of 13 with cinnamic or 4-fluorocinnamic acid gave the hybrids 14 and 16. Hydrolytic removal of the 1,2-isopropylidene protective group from 13 and 16, followed by cyclocondensation of the resulting lactols with Meldrum's acid, gave the [3.3.0]furofuranones 15 and 17. Using a similar reaction sequence, d-glucose was converted into the corresponding tetrazole derivatives 21 and 23. The key step in this synthesis is the cycloaddition of suitably functionalized urononitriles with azide anion to build the tetrazole ring. Some of the pseudo-C-nucleosides exhibited potent cytotoxicity against certain human tumour cell lines. Structural features important for the antiproliferative activity of these analogues were identified by SAR analysis. Biological effects of three compounds with strong cytotoxic response (14, 17 and 30) were investigated. The induction of apoptosis was assessed using several methods, including cell cycle flow cytometry analysis, double-fluorescent staining, and Annexin V flow cytometry. The results showed the potential of compound 14 to induce apoptosis in the most sensitive tumour cell line. The results suggest that these three compounds with strong selective cytotoxicity are good candidates for developing effective anticancer drugs.