Synthesis and in vitro antitumour activity of tiazofurin analogues with nitrogen functionalities at the C-2′ position

Abstract

Synthesis of three tiazofurin (1) isosteres with nitrogen functionalities at the C-2′ position (N3, NH2 and NH3+Cl−) has been achieved, in multistep sequences, starting from monoacetone d-glucose. A number of potential bioisosteres of 1 bearing acylamido functions at the C-2′ position have also been synthesized from the same sugar precursor. In vitro cytotoxicities of target molecules against a number of human tumour cell lines were recorded and compared with those observed for lead molecule 1. Some of the synthesized compounds showed potent in vitro antitumour activity, such as 2′-azido derivative 2, which is the most potent of all molecules under evaluation (IC50 0.004 μM against MCF-7 cells). Flow cytometry data suggest that cytotoxic effects of these compounds in the culture of K562 cells might be mediated by apoptosis, additionally revealing that these molecules induced changes in cell cycle distribution of these cells. Results of Western blot analysis indicate that the synthesized tiazofurin analogues induce apoptosis in a caspase-dependent way.