SYNTHESIS, ANTIPROLIFERATIVE, AND ANTIVIRAL ACTIVITY OF -D-RIBOFURANOSYL)PYRROLO[2,3-D]PYRIDAZIN-7(6H)-ONE AND RELATED DERIVATIVES

The synthesis of a-D-ribofuranosylpyrrolo[2,3-d]pyridazin-7(6H)-one (3 ) from the reaction of ethyl -cyano-1-beta-D-ribofuranosylpyrrole-2-ca rboxylate (10) and hydrazine is described. The 5:6 pyrrolo[2,3-d]pyrid azin-7(6H)-one structure of 3 was established via a three-step convers ion of 3 into ofuranosylpyrrolo[2,3-d]pyridazin-4,7(5H,6H)-dione (14), 4-Amino-3-chloro-1-beta-D-ribofuranosylpyrrolo [2,3-d]pyridazin-7(6H) -one (16) and 4-amino-3-bromo-l-beta-D-ribo-furanosylpyrrolo [2,3-d]py ridazin-7(6H)-one (18) were prepared via N-chlorosuccinimide or N-brom osuccinimide treatment of 3,5-tri-O-benzyl-beta-D-ribofuranosyl)pyrrol o[2,3- d]pyridazin-7(6H)-one (7) followed by a removal of the benzyl g roups with boron trichloride. Direct treatment of 3 with N-iodosuccini mide furnished a-D-ribofuranosylpyrrolo[2,3-d]pyridazin-7(6H)-one (19) . The antiproliferative activity of the compounds was determined in L1 210, H. Ep. 2 and several additional human tumor cell lines. In L1210 cells, the 3-halo-substituted compounds 16, 18, and 19 exhibited signi ficant cytotoxicity (IC50 = 0.2, 0.1, 0.08 mu M, respectively), in con trast to the 3-unsubstituted compound 3, which had only slight activit y. The greater antiproliferative activity of 18 and 19 in contrast to 3 was confirmed in H. Ep. 2 cells and KB cells. The antiviral evaluati on of these compounds revealed that compounds 16, 18, and 19 were acti ve against human cytomegalovirus in both plaque- and yield-reduction a ssays. However, this activity was only partially separated from cytoto xicity in human cell lines.