Sugar-modified derivatives of cytostatic 7-(het)aryl-7-deazaadenosines: 2′-C-methylribonucleosides, 2′-deoxy-2′-fluoroarabinonucleosides, arabinonucleosides and 2′-deoxyribonucleosides

A series of novel sugar-modified derivatives of cytostatic 7-hetaryl-7-deazaadenosines (2′-C-methylribonucleosides, 2′-deoxy-2′-fluoroarabinonucleosides, arabinonucleosides and 2′-deoxyribonucleosides) was prepared and screened for biological activity. The synthesis consisted of preparation of the corresponding sugar-modified 7-iodo-7-deazaadenine nucleosides and their aqueous-phase Suzuki-Miyaura cross-coupling reactions with (het)arylboronic acids or Stille couplings with hetarylstannanes in DMF. The synthesis of 7-iodo-7-deazaadenine nucleosides was based on a glycosidation of 6-chloro-7-iodo-7-deazapurine with a suitable sugar synthon or on an interconversion of 2′-OH stereocenter (for arabinonucleosides). Several examples of 2′-C-Me-ribonucleosides showed moderate anti-HCV activities in a replicon assay accompanied by cytotoxicity. Several 7-hetaryl-7-deazaadenine fluoroarabino- and arabinonucleosides exerted moderate micromolar cytostatic effects. The most active was 7-ethynyl-7-deazaadenine fluoroarabinonucleoside which showed submicromolar antiproliferative activity. However, all the sugar-modified derivatives were less active than the parent ribonucleosides.

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