7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action

0461356 - ÚOCHB 2017 RIV US eng J - Článek v odborném periodiku
Perlíková, Pavla - Rylová, G. - Nauš, Petr - Elbert, Tomáš - Tloušťová, Eva - Bourderioux, Aurelie - Poštová Slavětínská, Lenka - Motyka, K. - Doležal, D. - Znojek, P. - Nová, A. - Harvanová, M. - Džubák, P. - Šiller, M. - Hlaváč, J. - Hajdúch, M. - Hocek, Michal
7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action.
Molecular Cancer Therapeutics. Roč. 15, č. 5 (2016), s. 922-937. ISSN 1535-7163. E-ISSN 1538-8514
Grant CEP: GA ČR GAP207/11/0344; GA TA ČR(CZ) TE01020028; GA MŠMT(CZ) LO1304
Institucionální podpora: RVO:61388963
Klíčová slova: sugar-modified derivatives * cross-coupling reactions * ribosomal RNA synthesis
Kód oboru RIV: CC - Organická chemie
Impakt faktor: 5.764, rok: 2016

7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK-OV-3, BT-549, and HT-29 xenografts. The results indicate that AB61 is a promising compound with unique mechanism of action and deserves further development as an anticancer agent.
Trvalý link: http://hdl.handle.net/11104/0260969