Synthesis, antiproliferative, and antiviral activity of certain 4-aminopyrrolo[2,3-d]pyridazine nucleosides: an entry into a novel series of adenosine analogues.

The preparation of novel heterocyclic base modified adenosine analogues, the 4-aminopyrrolo[2,3-d]pyridazine nucleosides, is described. Crucial to their successful preparation was the use of the pyrrole glycoside intermediates 3-cyano-2-formyl-1-(2,3,5-tri-O-benzyl-beta-D-ribofuranosyl)pyrrole (11) and 3-cyano-2-formyl-1-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)pyrrole (17). Treatment of 11 and 17 with hydrazine dihydrochloride followed by treatment with boron trichloride provided 4-amino-1-beta-D-ribofuranosylpyrrolo[2,3-d]pyridazine (2) and 4-amino-1-beta-D-arabinofuranosylpyrrolo[2,3-d]pyridazine (3), respectively. 4-Amino-3-bromo-1-beta-D-ribofuranosylpyrrolo[2,3-d]-pyridazine (4) was prepared by a bromination of 4-amino-1-(2,3,5-tri-O-benzyl-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyri daz ine (12) and subsequent removal of the benzyl groups with boron trichloride. Compounds 2-4 were evaluated for antiproliferative and antiviral activity. The tubercidin analogue (2) and its arabinosyl derivative (3) were virtually inactive in all assays. In contrast, the 3-bromo analogue 4 inhibited growth of L1210 and H. Ep. 2 cells. Compound 4 was also active against human cytomegalovirus and herpes simplex virus type 1, but the antiviral activity was not completely separated from cytotoxicity.