Synthesis of 4′-substituted 2′-deoxy-4′-thiocytidines and its evaluation for antineoplastic and antiviral activities
2019; Elsevier BV; Volume: 75; Issue: 33 Linguagem: Inglês
10.1016/j.tet.2019.06.044
ISSN1464-5416
AutoresKazuhiro Haraguchi, Hiroki Kumamoto, K Konno, Hideki Yagi, Yutaka Tatano, Yuki Odanaka, Satoko Matsubayashi, Robert Snoeck, Graciela Andreï,
Tópico(s)Pneumocystis jirovecii pneumonia detection and treatment
Resumo4′-Azido- (7), 4′-C-fluoromethyl- (8) 4′-C-ethynyl- (9) and 4′-C-cyano- (10) 2′-deoxy-4′-thiocytidines have been synthesized. In this study, it was found that the isolated yield of 4′-thiouracil nucleoside 13 in a Lewis acid-promoted Vorbrüggen-type glycosidation utilizing 12 was better than that of the electrophilic glycosidation reaction between silylated uracil and 11. This improved result prompted us to perform the glycosidation utilizing 36 and 43 for the synthesis of 37 and 44. Introduction of the azido group was carried out by nucleophilic substitution in the 4′-benzoyloxy derivative 22a. On the other hand, 9 and 10 were synthesized by way of the chemical manipulation of the hydroxymethyl group at the 4′-position of 46. Evaluation of the antineoplastic activity of 2 and 7–10 against human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines revealed that 4′-azido- (7) and 4′-C-fluoromethyl- (8) derivatives exhibited cytotoxic activity whereas no cytotoxicity was observed in the 4′-C-ethynyl- (9) and 4′-C-cyano- (10) derivatives as well as the parent compound 2. Compound 7 was also found to possess promising antiviral activity against VZV and HSV-1 without any cytotoxity against HEL host cells. It is noteworthy that 7 exhibited potent inhibitory activities against the thymidine kinase-deficient (TK−) mutant of VZV and HSV-1.
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