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Three novel tiazofurin analogues having d-arabino stereochemistry and nitrogen functionalities at the C-2' position (5-7) have been designed and synthesized in multistep sequences, starting from d-glucose. The known d-xylo stereoisomer of 1 (compound 2) along with two new analogues bearing nitrogen functions at the C-3' (3 and 4) has also been synthesized from the same sugar precursor. The synthetic sequence consisted of the following three stages: (i) the multistep synthesis of suitably protected pentofuranosyl cyanides, (ii) the construction of ethyl thiazole-4-carboxylate part by cyclocondensation of thus obtained glycofuranosyl cyanides with l-cysteine ethyl ester followed by dehydrogenation, and (iii) the final transformation of the ethyl thiazole-4-carboxylates into the target tiazofurin analogues using the esters ammonolysis. The tiazofurin analogues were evaluated for their antitumour activities in cell-culture-based assays. Compounds 3, 4 (d-xylo) and 7 (d-arabino), showed remarkable antitumour activities, with IC 50 values in the range of 4-7 nM. Preliminary structure-activity relationship allowed identification of two analogues with antiproliferative activities exceeding that of the parent compound 1 for several orders of magnitude (e.g. 4: 1354-fold against Raji, 7: 309-fold against K562). Flow cytometry data and Western blot analysis suggested that cytotoxic effects of d-xylo stereoisomers in the culture of K562 cells caused changes in the cell cycle distribution, as well as the induction of apoptosis in caspase-dependent way. The increase of apoptotic cells percentage in treated samples is also confirmed with fluorescent double-staining method. Genotoxicity testing showed that the analogues with the xylo-configuration (2-4) are far less genotoxic than tiazofurin., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Three new 5'-O-acyl tiazofurin derivatives 2-4 were synthesized and evaluated for their antiproliferative activity against different tumour cell lines as well as for their ability to induce apoptosis in C6 cells in vitro. Apart of the antitumour assays, the cell membrane permeation of 2-4 and their intracellular metabolism in C6 cells in vitro was also studied in order to evaluate their potential as possible tiazofurin bioisosteres or prodrugs.