Rational Design and Synthesis of a Fluorinated Adenosine Derivative

Abstract

Pantothenate synthetase (PS), a member of adenosine acylation enzyme family, was the new target of anti-tuberculosis drug development. Employing bioisostere principle, 5'-O-{[(R)-2-hydroxy-3,3-dimethylbutanoyl]sulfamoyl}-2'-deoxy-2'-fluoroadenosine (1), a mimic of the PS catalyzed reaction intermediate, was rational designed by substituting the 2'-hydroxyl group of intermediate sugar ring with fluorine. This compound was synthesized using D-tertiary leucine and vidarabine as the starting materials by 9 steps of reaction, and its structure was fully characterized by 1 H NMR, 13 C NMR and HR-MS techniques.

Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase

“…The 2′-fluoroadenosine analogue 3 28 was also prepared starting from vidarabine 11 through regioselective protection of the less sterically encumbered 3′ and 5′-hydroxyl groups to yield 15 (Scheme 3). Fluorination of 15 with diethylaminosulfur trifluoride (DAST) afforded 16 .…”