The synthesis and biological activity profiling of a large series of diverse pyrrolo[2,3-d]pyrimidine 4'-C-methylribonucleosides bearing an (het)aryl group at position 4 or 5 is reported as well as the synthesis of several phosphoramidate prodrugs. These compounds are 4'-C-methyl derivatives of previously reported cytostatic hetaryl-7-deazapurine ribonucleosides. The synthesis is based on glycosylation of halogenated 7-deazapurine bases with 1,2-di-O-acetyl-3,5-di-O-benzyl-4-C-methyl-β-d-ribofuranose followed by cross-coupling and nucleophilic substitution reactions. The final compounds showed low cytotoxicity and several derivatives exerted antiviral activity against HCV or Dengue viruses at micromolar concentrations.

• Klíčová slova
• 4′-C-Methyl-ribonucleosides, Branched nucleosides, Nucleoside antivirals, Nucleosides, Prodrugs,
• MeSH
• antivirové látky chemická syntéza   farmakologie   MeSH
• Hepacivirus účinky léků   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• prekurzory léčiv chemická syntéza   farmakologie   MeSH
• protinádorové látky chemická syntéza   farmakologie   MeSH
• purinové nukleosidy chemická syntéza   farmakologie   MeSH
• purinové nukleotidy chemická syntéza   farmakologie   MeSH
• virus dengue účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• prekurzory léčiv MeSH
• protinádorové látky MeSH
• purinové nukleosidy MeSH
• purinové nukleotidy MeSH

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.

• MeSH
• antivirové látky farmakologie   MeSH
• nukleosidy * MeSH
• puriny farmakologie   MeSH
• ribonukleosidy * farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-deazapurine MeSH Prohlížeč
• antivirové látky MeSH
• nukleosidy * MeSH
• puriny MeSH
• ribonukleosidy * MeSH