SYNTHESIS AND BIOLOGICAL EVALUATION OF N-4-SUBSTITUTED IMIDAZO- AND V-TRIAZOLO[4,5-D]PYRIDAZINE NUCLEOSIDES

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.