Synthesis and Cytotoxic and Antiviral Profiling of Pyrrolo- and Furo-Fused 7-Deazapurine Ribonucleosides

0498520 - ÚOCHB 2019 RIV US eng J - Journal Article
Tokarenko, Anna - Lišková, B. - Smolen, Sabina - Táborská, N. - Tichý, Michal - Gurská, S. - Perlíková, Pavla - Frydrych, I. - Tloušťová, Eva - Znojek, P. - Mertlíková-Kaiserová, Helena - Poštová Slavětínská, Lenka - Pohl, Radek - Klepetářová, Blanka - Khalid, N. U. A. - Wenren, Y. - Laposa, R. R. - Džubák, P. - Hajdúch, M. - Hocek, Michal
Synthesis and Cytotoxic and Antiviral Profiling of Pyrrolo- and Furo-Fused 7-Deazapurine Ribonucleosides.
Journal of Medicinal Chemistry. Roč. 61, č. 20 (2018), s. 9347-9359. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR(CZ) GA16-00178S; GA TA ČR(CZ) TE01020028; GA MŠMT(CZ) LO1304; GA MŠMT(CZ) LM2015064
Grant - others:AV ČR(CZ) AP1501
Program: Akademická prémie - Praemium Academiae
Institutional support: RVO:61388963
Keywords : hepatitis C virus * adenosine kinase inhibitors * mitochondrial RNA polymerase
OECD category: Organic chemistry
Impact factor: 6.054, year: 2018
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.8b01258

Three series of isomeric pyrrolo- and furo-fused 7-deazapurine ribonucleosides were synthesized and screened for cytostatic and antiviral activity. The synthesis was based on heterocyclizations of hetaryl-azidopyrimidines to form the tricyclic heterocyclic bases, followed by glycosylation and final derivatizations through cross-coupling reactions or nucleophilic substitutions. The pyrrolo [2',3':4,5]pyrrolo [2,3-d]pyrimidine and furo[2',3':4,5]pyrrolo[2,3-d]pyrimidine ribonucleosides were found to be potent cytostatics, whereas the isomeric pyrrolo[3',2',4,5]pyrrolo[2,3-d]pyrimidine nucleosides were inactive. The most active were the methyl, methoxy, and methylsulfanyl derivatives exerting submicromolar cytostatic effects and good selectivity toward cancer cells. We have shown that the nucleosides are activated by intracellular phosphorylation and the nucleotides get incorporated to both RNA and DNA, where they cause DNA damage. They represent a new type of promising candidates for preclinical development toward antitumor agents.
Permanent Link: http://hdl.handle.net/11104/0291128