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Synthesis and Biological Profiling of Pyrazolo-Fused 7-Deazapurine Nucleosides
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SYSNO ASEP 0532387 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Synthesis and Biological Profiling of Pyrazolo-Fused 7-Deazapurine Nucleosides Author(s) Fleuti, Marianne (UOCHB-X) ORCID
Bártová, Kateřina (UOCHB-X)
Poštová Slavětínská, Lenka (UOCHB-X) RID
Tloušťová, Eva (UOCHB-X) RID, ORCID
Tichý, Michal (UOCHB-X) RID, ORCID
Gurská, S. (CZ)
Pavliš, P. (CZ)
Džubák, P. (CZ)
Hajdúch, M. (CZ)
Hocek, Michal (UOCHB-X) RID, ORCIDSource Title Journal of Organic Chemistry. - : American Chemical Society - ISSN 0022-3263
Roč. 85, č. 16 (2020), s. 10539-10551Number of pages 13 s. Language eng - English Country US - United States Keywords tyrosine kinase ; inhibitors ; adenosine Subject RIV CC - Organic Chemistry OECD category Organic chemistry R&D Projects GA19-08124S GA ČR - Czech Science Foundation (CSF) NV15-31984A GA MZd - Ministry of Health (MZ) LM2015064 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000563754800020 EID SCOPUS 85090890920 DOI 10.1021/acs.joc.0c00928 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2021 Electronic address https://doi.org/10.1021/acs.joc.0c00928
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