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Synthesis and Cytostatic and Antiviral Activities of 2′‐Deoxy‐2′,2′‐difluororibo‐ and 2′‐Deoxy‐2′‐fluororibonucleosides Derived from 7‐(Het)aryl‐7‐deazaadenines
Author(s) -
Perlíková Pavla,
Eberlin Ludovic,
Ménová Petra,
Raindlová Veronika,
Slavětínská Lenka,
Tloušťová Eva,
Bahador Gina,
Lee YuJen,
Hocek Michal
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300047
Subject(s) - chemistry , stereoselectivity , aryl , stereochemistry , mesylate , amination , diastereomer , reductive amination , combinatorial chemistry , organic chemistry , catalysis , alkyl
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 S N 2 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.