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

0498520 - ÚOCHB 2019 RIV US eng J - Článek v odborném periodiku
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
Grant CEP: GA ČR(CZ) GA16-00178S; GA TA ČR(CZ) TE01020028; GA MŠMT(CZ) LO1304; GA MŠMT(CZ) LM2015064
Grant ostatní: AV ČR(CZ) AP1501
Program: Akademická prémie - Praemium Academiae
Institucionální podpora: RVO:61388963
Klíčová slova: hepatitis C virus * adenosine kinase inhibitors * mitochondrial RNA polymerase
Obor OECD: Organic chemistry
Impakt faktor: 6.054, rok: 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.
Trvalý link: http://hdl.handle.net/11104/0291128