Structure based design, synthesis and in  vitro antitumour activity of tiazofurin stereoisomers with nitrogen functions at the C-2' or C-3' positions.

Structure based design, synthesis and in vitro antitumour activity of tiazofurin stereoisomers with nitrogen functions at the C-2' or C-3' positions. Eur J Med Chem. 2019 Sep 18;183:111712 Authors: Kojić V, Popsavin M, Spaić S, Jakimov D, Kovačević I, Svirčev M, Aleksić L, Zelenović BS, Popsavin V Abstract 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 IC50 values in the range of 4-7 nM. Preliminary structure-activity relationship allowed identification ...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research