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

0532387 - ÚOCHB 2021 RIV US eng J - Journal Article
Fleuti, Marianne - Bártová, Kateřina - Poštová Slavětínská, Lenka - Tloušťová, Eva - Tichý, Michal - Gurská, S. - Pavliš, P. - Džubák, P. - Hajdúch, M. - Hocek, Michal
Synthesis and Biological Profiling of Pyrazolo-Fused 7-Deazapurine Nucleosides.
Journal of Organic Chemistry. Roč. 85, č. 16 (2020), s. 10539-10551. ISSN 0022-3263. E-ISSN 1520-6904
R&D Projects: GA ČR(CZ) GA19-08124S; GA MZd(CZ) NV15-31984A; GA MŠMT(CZ) LM2015064
Grant - others:AV ČR(CZ) AP1501
Program: Akademická prémie - Praemium Academiae
Institutional support: RVO:61388963
Keywords : tyrosine kinase * inhibitors * adenosine
OECD category: Organic chemistry
Impact factor: 4.354, year: 2020
Method of publishing: Limited access
https://doi.org/10.1021/acs.joc.0c00928

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.
Permanent Link: http://hdl.handle.net/11104/0310889