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 Dec 1:183:111712. doi: 10.1016/j.ejmech.2019.111712.
- 1. Oncology Institute of Vojvodina, Faculty of Medicine, University of Novi Sad, Put Dr Goldmana 4, 21204, Sremska Kamenica, Serbia.
- 2. Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, Novi Sad, Serbia. Electronic address: [email protected].
- 3. Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, Novi Sad, Serbia.
- 4. Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, Novi Sad, Serbia; Serbian Academy of Sciences and Arts, Knez Mihajlova 35, 11000, Belgrade, Serbia.
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 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.