Synthesis and biological evaluation of N4-substituted imidazo- and v-triazolo[4,5-d]pyridazine nucleosides.
The chemical synthesis of certain N4-substituted imidazo[4,5-d]pyridazine and v-triazolo[4,5-d]-pyridazine nucleosides is described. In both series, the 4-chloro analogues, i.e., 4-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazo[4,5-d]pyr idazine (5a) and 4-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-v-triazolo[4,5- d]pyridazine (5b), were used as synthons to the target nucleosides. Nucleoside 5b was far more reactive toward nucleophilic displacements than 5a. Attempted deprotection of 5b was always accompanied 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 substrate/inhibition studies with certain purine-metabolizing enzymes. The corresponding adenosine analogues, i.e., 2-aza-3-deazaadenosine (6a) and 2,8-diaza-3-deazaadenosine (6b), were very slowly reacting substrates and weak inhibitors of bovine adenosine deaminase, whereas the inosine analogues were highly resistant to human purine nucleoside phosphorylase. The 4-benzylamino derivatives were weak inhibitors of adenosine transport into human erythrocytes. The inosine, adenosine, and selected N4-substituted analogues exhibited no in vitro toxicity toward murine L1210 leukemia and B16 melanoma cells.
Bussolari
J C
JC
Department of Medicinal Chemistry, University of Rhode Island, Kingston 02881.
Ramesh
K
K
Stoeckler
J D
JD
Chen
S F
SF
Panzica
R P
RP
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D058892:Adenosine Deaminase Inhibitors; D000970:Antineoplastic Agents; D009705:Nucleosides; D011724:Pyridazines