Synthesis, Antiproliferative, and Antiviral Activity of 4-Amino-1-(β-D-ribofuranosyl)pyrrolopyridazin-7(6H)-one and Related Derivatives

Article abstract of DOI:10.1021/jm00076a011

The synthesis of 4-amino-1-β-D-ribofuranosylpyrrolo<2,3-d>pyridazin-7(6H)-one (3) from the reaction of ethyl 3-cyano-1-β-D-ribofuranosylpyrrole-2-carboxylate (10) and hydrazine is described.The 5:6 pyrrolo<2,3-d>pyridazin-7(6H)-one structure of 3 was established via a three-step conversion of 3 into 1-β-D-ribofuranosylpyrrolo<2,3-d>pyridazin-4,7(5H,6H)-dione (14). 4-amino-3-chloro-1-β-D-ribofuranosylpyrrolo<2,3-d>pyridazin-7(6H)-one (16) and 4-amino-3-bromo-1-β-D-ribofuranosylpyrrolo<2,3-d>pyridazin-7(6H)-one (18) were prepared via N-chlorosuccinimide or N-bromosuccinimide treatment of 4-amino-1-(2,3,5-tri-O-benzyl-β-D-ribofuranosyl)pyrrolo<2,3-d>pyridazin-7(6H)-one (7) followed by a removal of the benzyl groups with boron trichloride.Direct treatment of 3 with N-iodosuccinimide furnished 4-amino-3-iodo-1-β-D-ribofuranosylpyrrolo<2,3-d>pyridazin-7(6H)-one (19).The antiproliferative activity of the compounds was determined in L1210, H.Ep. 2 and several additional human tumor cell lines.In L1210 cells, the 3-halosubstituted compounds 16, 18, and 19 exhibited significant cytotoxicity (IC50 = 0.2, 0.1, 0.08 μM, respectively), in contrast to the 3-unsubstituted compound 3, which had only slight activity.The greater antiproliferative activity of 18 and 19 in contrast to 3 was confirmed in H.Ep. 2 cells and KB cells.The antiviral evaluation of these compounds revealed that compounds 16, 18, and 19 were active against human cytomegalovirus in both plaque- and yield-reduction assays.However, this activity was only partially separated from cytotoxicity in human cell lines.