Synthesis and antiproliferative activity of thiazole bioisosteres of goniofufurone and 7-epi-goniofufurone

Abstract

Several new goniofufurone (1) and 7-epi-goniofufurone (2) mimics in which the benzene ring has been replaced with a thiazole residue have been designed, synthesized and evaluated for their antiproliferative activity against a panel of human tumour cell lines. The key steps of the synthesis represent the initial condensation of suitably protected furanose urononitriles with cysteine ethyl ester hydrochloride, followed by the subsequent oxidation of resulting C-4′ epimeric thiazolines with BrCCl₃ and DBU, to build up the thiazole ring. Biological studies have shown that the HeLa cell line is most sensitive to the action of synthesized analogues with IC₅₀ values in the range of 0.01–7.67 μM. The most active compound in this cell culture was 7-epi-goniofufurone mimic 28, with a thiazole-carboxamide function at C-7 and a benzyloxy group at the C-5 position. Compound 28 exhibited 89-fold higher antiproliferative potency in this cell line than lead 2 and was 7-fold more active than the commercial antitumour agent doxorubicin. A SAR study identified structural features responsible for the antiproliferative activity of synthesized analogues. The analogues 3–28 are completely inactive toward the normal MRC-5 cell line. Their selectivity indexes (SI) range from 4.1 to 17,470.7.