Abstract
A unified synthetic strategy accessing novel 3'-fluorinated purine nucleoside derivatives and their biological evaluation were achieved. Novel 3’-fluorinated analogues were constructed from a common 3’-deoxy-3’-fluororibofuranose intermediate. Employing Suzuki and Stille cross-coupling reactions, fifteen 3’-fluororibose purine nucleosides 1–15 and eight 3’-fluororibose 2-chloro/2-aminopurine nucleosides 16–23 with various substituents at position 6 of the purine ring were efficiently synthesized. Furthermore, 3’-fluorine analogs of natural products nebularine and 6-methylpurine riboside were constructed via our convergent synthetic strategy. Synthesized nucleosides were tested against HT116 (colon cancer) and 143B (osteosarcoma cancer) tumor cell lines. We have demonstrated 3’-fluorine purine nucleoside analogues display potent tumor cell growth inhibition activity at sub- or low micromolar concentration.
Highlights
Antimetabolites are extremely useful for the treatment of cancers and viral infections and are one of the largest classes of drugs
The design of new antimetabolites is an active field of research and several nucleoside derivatives have recently come to market such as gemcitabine, capecitabine, and decitabine [4,5,6]
Current strategies to the synthesis of 3’-fluorine and 6-substituted purine require harsh conditions and laborious protecting group manipulation that results in low product yields
Summary
Antimetabolites are extremely useful for the treatment of cancers and viral infections and are one of the largest classes of drugs. Current strategies to the synthesis of 3’-fluorine and 6-substituted purine require harsh conditions and laborious protecting group manipulation that results in low product yields. This key intermediate 25 can be used to synthesize a variety of 3’-fluoro-modified nucleoside derivatives, and it was utilized for the synthesis of all analogues reported .
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