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

被引:4
作者
Kojic, Vesna [1 ]
Popsavin, Mirjana [2 ]
Spaic, Sasa [2 ]
Jakimov, Dimitar [1 ]
Kovacevic, Ivana [2 ]
Svircev, Milos [2 ]
Aleksic, Lidija [1 ]
Sreco Zelenovic, Bojana [2 ]
Popsavin, Velimir [2 ,3 ]
机构
[1] Univ Novi Sad, Fac Med, Oncol Inst Vojvodina, Put Dr Goldmana 4, Sremska Kamenica 21204, Serbia
[2] Univ Novi Sad, Fac Sci, Dept Chem Biochem & Environm Protect, Trg Dositeja Obradovica 3, Novi Sad, Serbia
[3] Serbian Acad Arts & Sci, Knez Mihajlova 35, Belgrade 11000, Serbia
关键词
Tiazofurin analogues; De novo synthesis; Cytotoxicity; Flow cytometry; Comet assay; Double fluorescent staining; INOSINE MONOPHOSPHATE DEHYDROGENASE; C-NUCLEOSIDES; ANALOGS; INHIBITORS; ASSAY;
D O I
10.1016/j.ejmech.2019.111712
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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. (C) 2019 Elsevier Masson SAS. All rights reserved.
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页数:11
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