Synthesis and cytostatic and antiviral activities of 2 '-deoxy-2 ',2 '-difluororibo- and 2 '-deoxy-2 '-fluororibonucleosides derived from 7-(het)aryl-7-deazaadenines

0393973 - ÚOCHB 2014 RIV DE eng J - Článek v odborném periodiku
Perlíková, Pavla - Eberlin, Ludovic - Ménová, Petra - Raindlová, Veronika - Slavětínská, Lenka - Tloušťová, Eva - Bahador, G. - Lee, Y. J. - Hocek, Michal
Synthesis and cytostatic and antiviral activities of 2 '-deoxy-2 ',2 '-difluororibo- and 2 '-deoxy-2 '-fluororibonucleosides derived from 7-(het)aryl-7-deazaadenines.
ChemMedChem. Roč. 8, č. 5 (2013), s. 832-846. ISSN 1860-7179. E-ISSN 1860-7187
Grant CEP: GA ČR GAP207/11/0344
Institucionální podpora: RVO:61388963
Klíčová slova: 7-deazapurines * antiviral agents * cytostatics * fluorinated derivatives * nucleosides
Kód oboru RIV: CC - Organická chemie
Impakt faktor: 3.046, rok: 2013

A series of sugar-modified derivatives of cytostatic 7-heteroaryl-7-deazaadenosines (2-deoxy-2-fluororibo- and 2-deoxy-2,2-difluororibonucleosides) bearing an aryl or heteroaryl group at position7 was prepared and screened for biological activity. The difluororibonucleosides were prepared by non- stereoselective glycosidation of 6-chloro-7-deazapurine with benzoyl-protected 2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl-1-mesylate, followed by amination and aqueous Suzuki cross-couplings with (het)arylboronic acids. The fluororibo derivatives were prepared by aqueous palladium-catalyzed cross-coupling reactions of the corresponding 7-iodo-7-deazaadenine 2-deoxy-2-fluororibonucleoside 20 with (het)arylboronic acids. The key intermediate 20 was prepared by a six-step sequence from the corresponding arabinonucleoside by selective protection of 3- and 5-hydroxy groups with acid-labile groups, followed by stereoselective SN2 fluorination and deprotection. Some of the title nucleosides and 7-iodo-7-deazaadenine intermediates showed micromolar cytostatic or anti-HCV activity. The most active were 7-iodo and 7-ethynyl derivatives. The corresponding 2-deoxy-2,2-difluororibonucleoside 5-O-triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymerase.
Trvalý link: http://hdl.handle.net/11104/0222332