NUCLEOSIDES AND NUCLEOTIDES .141. CHEMICAL-STABILITY OF A NEW ANTITUMOR NUCLEOSIDE, O-2'-DEOXY-1-BETA-D-ARABINO-PENTOFURANOSYLCYTOSINE IN ALKALINE-MEDIUM - FORMATION OF YANO-2'-DEOXY-1-BETA-D-RIBO-PENTOFURANOSYLCYTOSINE AND ITS ANTITUMOR-ACTIVITY
A. Azuma et al., NUCLEOSIDES AND NUCLEOTIDES .141. CHEMICAL-STABILITY OF A NEW ANTITUMOR NUCLEOSIDE, O-2'-DEOXY-1-BETA-D-ARABINO-PENTOFURANOSYLCYTOSINE IN ALKALINE-MEDIUM - FORMATION OF YANO-2'-DEOXY-1-BETA-D-RIBO-PENTOFURANOSYLCYTOSINE AND ITS ANTITUMOR-ACTIVITY, Journal of medicinal chemistry, 38(17), 1995, pp. 3391-3397
We have designed o-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (C
NDAC) as a potential mechanism-based DNA-strand-breaking nucleoside, w
hich showed potent tumor cell growth inhibitory activity against vario
us human tumor cell lines in vitro and in vive. When measuring the pK(
a) of the 2'alpha-proton of CNDAC, we found that CNDAC epimerized to 2
'-C-cyano-2'-deoxy-1 -beta-D-ribo-pentofuranosylcytosine (CNDC) with c
oncomitant degradation of both CNDAC and CNDC to cytosine and anhydro-
2-C-cyano-2-deoxy-D-erythro-pent-1-enitol. Kinetic analysis of these r
eactions showed that abstraction of the acidic 2'-proton of CNDAC and
CNDC initiated the reactions, which quickly reached an equilibrium. In
the equilibrium, a concentration ratio of CNDAC and CNDC was about 3:
5. Concomitant degradation of these nucleosides was found to be rather
slow. Deuterium incorporation experiments with CNDAC in a D2O buffer
suggested the mechanism of the beta-elimination reactions is an E1cB t
ype. These epimerization and degradation reactions were found even in
neutral conditions (pH 7.5) and also occurred in RPMI 1640 cell cultur
e medium. The discovery of which nucleoside possesses the predominate
tumor cell growth inhibitory activity was important. While both nucleo
sides showed potent tumor cell growth inhibitory activity against thre
e human tumor cell lines (colon carcinoma WiDr, small cell lung carcin
oma SBC-5, and stomach carcinoma MKN-74 cells) in 48 h of incubation,
in 20 min of incubation, CNDAC was 11-50 times more effective than CND
C. In vivo antileukemic activity of these nucleosides against a mouse
P388 model, CNDAC was obviously superior to CNDC. Therefore, tumor cel
l growth inhibitory activity of CNDC could be related to the quantity
of CNDAC produced in the tumor cells by the equilibrium initiated by t
he abstraction of the acidic 2'-proton of CNDC.