Synthesis and Cytostatic and Antiviral Activities of 2′‐Deoxy‐2′,2′‐difluororibo‐ and 2′‐Deoxy‐2′‐fluororibonucleosides Derived from 7‐(Het)aryl‐7‐deazaadenines |
| |
Authors: | Dr Pavla Perlíková Ludovic Eberlin Petra Ménová Veronika Raindlová Dr Lenka Slavětínská Eva Tlou??ová Dr Gina Bahador Dr Yu‐Jen Lee Prof?Dr Michal Hocek |
| |
Affiliation: | 1. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2, 16610 Prague 6 (Czech Republic);2. Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404 (USA);3. Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 12843 Prague 2 (Czech Republic) |
| |
Abstract: | 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 position 7 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 α. |
| |
Keywords: | 7‐deazapurines antiviral agents cytostatics fluorinated derivatives nucleosides |
|
|