Thienopyrrolo[2, 3‐d]pyrimidines, New Tricyclic Nucleobase Analogues: Synthesis and Biological Activities

Abstract

Three isomeric series of 4‐substituted thieno‐fused 7‐deazapurine nucleobases were synthesized by palladium catalyzed couplings or nucleophilic substitutions from protected key‐intermediate 4‐chlorothienopyrrolopyrimidines. Most final nucleobases exerted micromolar activity against hepatitis C virus and respiratory syncytial virus, as well as some in vitro cytostatic activities against several cancer and leukemia cell lines. Three new nucleosides derived from 8H‐thieno[3′, 4′:4,5]pyrrolo[2, 3‐d]pyrimidine were also synthesized and were significantly more cytostatic than corresponding nucleobases, with activities in submicromolar range and low toxicity to normal cycling fibroblasts.

Pyrido-Fused Deazapurine Bases: Synthesis and Glycosylation of 4-Substituted 9H-Pyrido[2′,3′:4,5]- and Pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidines

“…The reactions proceeded smoothly within 16 h to give the desired hetaryl derivatives 10f–h and 11f–h (Scheme and Table ). Compared with previously prepared modified thienopyrrolopyrimidines, where nucleophilic substitutions did not proceed well on unprotected heterocycles, no protection of pyrrole nitrogen in pyridopyrrolopyrimidines was necessary, and although the yields of some of these reactions were rather moderate, they were mostly better or comparable to the three-step sequence (protection with the 2-trimethylsilylethoxymethyl [SEM] group, substitution, and deprotection) used previously for thienopyrrolopyrimidines …”

“… 11 , 12 Different isomeric thieno-fused deazapurines exerted moderate antiviral or cytotoxic activities. 13 Out of the four possible isomers of pyrido-fused deazapurines, the most intensively studied were pyrido[4′,3′:4,5]pyrrolo[2,3- d ]pyrimidines which include inhibitors of CDK4 ( 1 ) 14 or CHK1 ( 2 ) 15 kinases with antitumor activities ( Figure 1 ). Some pyrido[3′,4′:4,5]pyrrolo[2,3- d ]pyrimidine derivatives are ligands of the GABA A receptor, 16 whereas pyrido[2′,3′:4,5]pyrrolo[2,3- d ]pyrimidines (e.g., 3 ) were patented as bromodomain inhibitors.…”

“…Benzo-fused deazapurines (pyrimido­[4,5- b ]­indoles) have been reported as inhibitors of tyrosine kinase and thymidylate synthase, inhibitors of EGFR and VEGFR2, , and BET bromodomain . Some other derivatives exhibited microtubule depolymerizing and stabilizing effects , or antimicrobial , or antiparasitic activities. , Different isomeric thieno-fused deazapurines exerted moderate antiviral or cytotoxic activities . Out of the four possible isomers of pyrido-fused deazapurines, the most intensively studied were pyrido­[4′,3′:4,5]­pyrrolo­[2,3- d ]­pyrimidines which include inhibitors of CDK4 ( 1 ) or CHK1 ( 2 ) kinases with antitumor activities (Figure ).…”