A. Pískala, N. B. Hanna, J. Zajicek
1989
Citations
0
Influential Citations
4
Citations
Journal
Collection of Czechoslovak Chemical Communications
Abstract
Reaction of N-ethoxycarbonylguanidine III with 2,3.5-tri-O-benzoyl-l3-o-ribosyl isocyanate (II) afforded N-ethoxycarbonylamidinourea I V, 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 S-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 oxida tion of tribenzoyl-S-azacytidine IX with hydrogen peroxide in acetic acid. Methanolysis of blocked nucleoside V gave ribosylammelide (VI). The measurement of 1 H NMR spectra of 6-amino-S -azacytidine (l) revealed a marked preference of g + (SO~o) rotamer around C(S')-C(4') bond, a predominance of S conformation of the ribose ring (Keq 2'12) and a preference of anti conforma tion around the C- N glycosyl bond. These data indicate a conformational resemblance of 6-amino-S-azacytidine (1) to purine nucleosides. 6-Amino-5-azacytidine (l) inhibits the growth of bacteria E. coli while 6-methoxy and 6-oxo derivatives VIII and VI, respectively, are bacterio statically inactive. 6-Amino-5-azacytidine (l) had an 1Dso of 33·9 ~M against CCRF-CEM cells and inhibited the growth of WI-L2 cells by 39% at 100 11M but did not inhibit L1210 and LoVo/L cells at --:;: lOa ~M concentration. 5-Azacytidine ' is used in clinical treatment of acute leukemia2 and 2'-deoxy-5-azacytidine 3 has also been shown to be an efrective antileukemic agent in children 4 . 1-/3-D-Arabinofuranosyl-5-azacytosine was found to display a pronounced anti leukemic activiti y5.6. Both, 5-azacytidine and 2'-deoxy-5-azacytidine are very useful experimental tools in cell and molecular biology 7. Wide-spectrum of biological activity of the mentioned 5-azacytosine nucleosides stimulated our interest in sub stituted congeners of these compounds. Recently, N4 -substituted derivatives of 5-azacytidine and 2'-dcoxy-5-azacytidine have been prepared in our laboratory and their antibacterialS and antisecretory9 activity have been described. In continuation of the study of substituted 5-azapyrimidine nucleosides we were also interested in 6-amino-5-azacytidine (I). In this paper we wish to present the preparation of this compound, its molecular conformation and biological activity. The preparation of 6-amino-5-azacytidine (1) was formerly also included in two symposial presenta tions 1o,l1.