Synthesis and Cytostatic and Antiviral Activities of 2-Deoxy-2,2-difluororibo- and 2-Deoxy-2-fluororibonucleosides Derived from 7-(Het)aryl-7-deazaadenines

摘要

A series of sugar-modified derivatives of cytostatic 7-hetero-aryl-7-deazaadenqsines (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. glycpsidation of ,6-chl,oro-7-deazapurine with benzoyl-protected ,2-deoxy-2,2-difluoro-b-erythro-pentofurano-syl-1-mesylate, followed by amination and aqueous Suzuki cross-couplings with (het)arylboronicacids. The fluororibo derivatives were prepared by aqueous palladium-catalyzed cross-coupling reactions of the ! corresponding 7~iodo-7-deaza-adenine 2'-deoxy-2'-fluorpribonucleoside 20 with (het)arylbor- onic 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_N2 fluorination and de-protection. Some of the title nucleosides and 7-iodo-7-deaza-adenine intermediates showed micromolar cytostatic or antl-HCV activity. The most active were 7-iodo and 7-ethynyt derivatives. The corresponding 2'-deoxy-2',2'-difluororiboriucleoside 5'-O-triphosphates were found to.be, good substrates for bacterial DNA polymerases, but are inhibitors of human polymerases.