NUCLEOSIDES AND NUCLEOTIDES .123. SYNTHESIS OF -DEOXY-2-ISOCYANO-BETA-D-ARABINOFURANOSYL)CYTOSINE AND RELATED NUCLEOSIDES AS POTENTIAL ANTITUMOR AGENTS
A. Matsuda et al., NUCLEOSIDES AND NUCLEOTIDES .123. SYNTHESIS OF -DEOXY-2-ISOCYANO-BETA-D-ARABINOFURANOSYL)CYTOSINE AND RELATED NUCLEOSIDES AS POTENTIAL ANTITUMOR AGENTS, Journal of medicinal chemistry, 36(26), 1993, pp. 4190-4194
eoxy-2'-isocyano-1-beta-D-arabinofuranosylcytosine (8, NCDAC) has been
synthesized as a potential antitumor antimetabolite from a correspond
ing 2'-azido-2'-deoxy-1-beta-D-arabinofuranosyluracil derivative 2a. U
racil and thymine analogues 6a and 6b of 8 were also prepared. Attempt
s to synthesize 2'-deoxy-2'-isocyanocytidine (14b) failed due to the i
nsertion of the 2'-alpha isocyano group into the 3'-OH group, affordin
g the 2',3'-oxazoline derivative 15b. Stability of the isocyano deriva
tive 6a and 2',3'-oxazoline derivative 15a under basic and acidic cond
itions were examined. The isocyano group in 6a was stable in basic con
ditions but unstable even in weakly acidic conditions to furnish the c
orresponding 2'-beta formamide derivative 17. Compound 15a was easily
hydrolyzed the corresponding 2'-alpha formamide derivative 16 on treat
ment with H2O at room temperature. The cytotoxicity of 8, 6a, and 6b w
as examined in mouse and human tumor cells in vitro and compared with
that of ara-C. Of these nucleosides, 8 was moderately cytotoxic to the
se cell lines. In vivo antitumor activity of 8 against Lewis lung carc
inoma cells was also investigated and 8 showed only moderate tumor vol
ume inhibition.