Synthesis and Biological Profiling of Pyrazolo-Fused 7‑Deazapurine Nucleosides

A series of 8-substituted 1-methyl-1,4-dihydropyrazolo­[3′,4′:4,5]­pyrrolo­[2,3-d]­pyrimidine (methylpyrazolo-fused 7-deazapurine) ribonucleosides
have been designed and synthesized. Two synthetic approaches to the
key heterocyclic aglycon 7, (i) a six-step classical
heterocyclization starting from 5-chloro-1-methyl-4-nitropyrazole
and (ii) a three-step cross-coupling and cyclization approach starting
from the zincated 4,6-dichloropyrimidine, gave comparable total yields
of 18% vs 13%. The glycosylation of 7 was attempted by
three different methods but only the Vorbrüggen silyl-base
protocol was efficient and stereoselective to give desired β-anomeric
nucleoside intermediate 17A. Its nucleophilic substitutions
or cross-coupling reactions at position 8 and deprotection of the
sugar moiety gave eight derivatives of pyrazolo-fused deazapurine
ribonucleosides, some of which were weakly fluorescent. Methyl, amino,
and methylsulfanyl derivatives exerted submicromolar cytotoxic effects
in vitro against a panel of cancer and leukemia cell lines as well
as antiviral effects against hepatitis C virus in the replicon assay.