Jc. Bussolari et al., SYNTHESIS AND BIOLOGICAL EVALUATION OF N-4-SUBSTITUTED IMIDAZO- AND V-TRIAZOLO[4,5-D]PYRIDAZINE NUCLEOSIDES, Journal of medicinal chemistry, 36(25), 1993, pp. 4113-4120
The chemical synthesis of certain N-4-substituted imidazo [4,5-d]pyrid
azine and v-triazolo[4,5-d]pyridazine nucleosides is described. In bot
h series, the 4-chloro analogues, i.e., 5-tri-O-acetyl-beta-D-ribofura
nosyl)imidazo[4,5-d] pyridazine (5a) and -O-acetyl-beta-D-ribofuranosy
l)-v-triazolol[4,5-d] pyridazine (5b),were used as synthons to the tar
get nucleosides. Nucleoside 5b was far more reactive toward nucleophil
ic displacements than 5a. Attempted deprotection of 5b was always acco
mpanied with displacement of the 4-chloro substituent, whereas 5a was
conveniently deacetylated without loss of the chloro group. Biological
evaluation of the title nucleosides included antitumor studies and su
bstrate/inhibition studies with certain purine-metabolizing enzymes. T
he corresponding adenosine analogues, i.e., 2-aza-3-deazaadenosine (6a
) and 2,8-diaza-3-deazaadenosine (6b), were very slowly reacting subst
rates and weak inhibitors of bovine adenosine deaminase, whereas the i
nosine analogues were highly resistant to human purine nucleoside phos
phorylase. The 4-benzylamino derivatives were weak inhibitors of adeno
sine transport into human erythrocytes. The inosine, adenosine, and se
lected N-4-substituted analogues exhibited no in vitro toxicity toward
murine L1210 leukemia and B16 melanoma cells.