Synthesis and antiproliferative activity of new thiazole hybrids with [3.3.0]furofuranone or tetrahydrofuran scaffolds

Abstract

New thiazole hybrids were synthesized and evaluated for their in vitro cytotoxicity against a panel of human malignant cell lines. The key steps in the synthesis of hybrids 3-7 involved the initial condensation of appropriate aldononitriles with cysteine ethyl ester hydrochloride, followed by subsequent treatment of resulting thiazolines with DBU to form the thiazole ring. Bioiso-steres 8 and 14 have been prepared after the stereoselective addition of 2-(tri-methylsilyl)thiazole to the hemiacetals obtained by periodate cleavage of terminal diol functionality in the suitably protected D-glucose derivatives. The obtained analogues showed various antiproliferative activities in the cultures of several tumour cell lines. Hybrid 6 was the most potent in HeLa cells, exhibiting more than 10 and 4 times stronger activity than both leads 1 and 2, respectively. The most active compound in Raji cells was hybrid 12, which was nearly 2-fold more potent than the clinical antitumour drug doxorubicin. All analogues were more potent in A549 cells with respect to lead 1, while compounds 6 and 7 were slightly more active than DOX. Preliminary SAR analysis revealed that the presence of a cinnamate group at the C-3 position in analogues of type 7 increases the activity of resulting molecular hybrids.