Collect. Czech. Chem. Commun. 1989, 54, 2502-2512

Synthesis, molecular conformation and biological activity of 6-amino-5-azacytidine

Alois Pískala, Naeem B. Hanna, Jaroslav Zajíček and Alois Čihák

Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, 166 10 Prague 6


Reaction of N-ethoxycarbonylguanidine III with 2,3,5-tri-O-benzoyl-β-D-ribosyl isocyanate (II) afforded N-ethoxycarbonylamidinourea IV, which was cyclized by bis(trimethylsilyl)acetamide to the 6-ethoxy derivative VII. Ammono- and methanolysis of intermediate VII yielded 6-amino and 6-methoxy derivatives of 5-azacytidine I and VIII, respectively. Reaction of amidinourea IV with a mixture of chlorotrimethylsilane and triethylamine gave the blocked nucleoside V which was also formed by dealkylation of 6-ethoxy derivative VII with chlorotrimethylsilane or oxidation of tribenzoyl-5-azacytidine IX with hydrogen peroxide in acetic acid. Methanolysis of blocked nucleoside V gave ribosylammelide (VI). The measurement of 1H NMR spectra of 6-amino-5-azacytidine (I) revealed a marked preference of g+ (80%) rotamer around C(5')-C(4') bond, a predominance of S conformation of the ribose ring (Keq 2.12) and a preference of anti conformation around the C-N glycosyl bond. These data indicate a conformational resemblance of 6-amino-5-azacytidine (I) to purine nucleosides. 6-Amino-5-azacytidine (I) inhibits the growth of bacteria E. coli while 6-methoxy and 6-oxo derivatives VIII and VI, respectively, are bacteriostatically inactive. 6-Amino-5-azacytidine (I) had an ID50 of 33.9 μM against CCRF-CEM cells and inhibited the growth of WI-L2 cells by 39% at 100 μM but did not inhibit L1210 and LoVo/L cells at ⪬ 100μM concentration.