The synthesis and biological evaluation of pyrrolo(2,3 -d)pyridazine and pyrrolo(2,3 -d)pyridazin-7-one nucleosides.

The synthesis and isolation from natural sources of heterocyclic base modified adenosine analogs has provided numerous agents with significant biological activity. The present investigation described the synthesis of 3,7-dideaza-2-azapurine nucleoside analogs of adenosine. 4-Amino-1-($\beta$-D-ribofuranosyl)pyrrolo(2,3-d) pyridazine, a structural isomer of the naturally occurring nucleoside antibiotic tubercidin, and 4-amino-1-($\beta$-D-arabinofuranosyl)pyrrolo (2,3-d) pyridazine were prepared via a ring annulation of 3-cyano-2-formyl-1-glycosylpyrrole precursors followed by a removal of the sugar blocking groups. Elaboration of 4-amino-1-(2,3,5-tri-O-benzyl-$\beta$-D-ribofuranosyl)pyrrolo (2,3-d) pyridazine to 4-amino-3-bromo-1-($\beta$-D-ribofuranosyl)pyrrolo (2,3-d) pyridazine was accomplished by bromination followed by removal of the benzyl groups. Another adenosine analog, 4-amino-1-($\beta$-D-ribofuranosyl)pyrrolo (2,3-d) pyridazin-7-one, was prepared by the ring annulation of ethyl 3-cyano-1-($\beta$-D-ribofuranosyl)pyrrole-2-carboxylate with hydrazine. Halogenation of the intact bicyclic pyrrolo (2,3-d) pyridazin-7-one nucleoside provided the three C-3 halogenated (chloro, bromo, and iodo) analogs. The synthesis of sugar modified analogs (the arabinofuranosyl, the 2$\sp\prime$-deoxyribofuranosyl, the 2$\sp\prime,3\sp\prime$-dideoxyribofuranosyl, and the (1,3-dihydroxy-2-propoxy)methyl) in the series bearing the base 4-aminopyrrolo (2,3-d) pyridazin-7-one were carried out in an effort to obtain antiviral agents with decreased cytotoxicity. The 3-bromo derivatives of each of these sugar modified analogs were prepared by treatment with either bromine or N-bromosuccinimide. Several target nucleosides displayed significant cytotoxicity when they were evaluated for their antiproliferative effects against L1210 cell cultures. 4-Amino-3-halo-1-($\beta$-D-ribofuranosyl)pyrrolo (2,3-d) pyridazin-7-one nucleosides proved to be the most cytotoxic nucleosides in this investigation. In addition to the evaluation of their antiproliferative effects, the target nucleosides were also evaluated for their antiviral effects in plaque reduction assays. The presence of a halogen at C-3 and an oxo moiety at C-7 were observed to be necessary for antiviral activity.Ph.D.Pharmacy sciencesPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128785/2/9208468.pd