Total Synthesis of Uracil Analogues of Sinefungin

J Med Chem. 1992 Jan;35(1):63-7. doi: 10.1021/jm00079a007.

Abstract

Analogues of sinefungin derivatives 18a and 18b have been prepared from uridine and L-aspartic acid. The key step in the synthesis was the coupling of the radical derived from 14 with the unsaturated amide 13. The latter was produced from the known N-hydroxy-2-thiopyridone ester of L-aspartic acid 12 with the olefin 11. Thus, the essential carbon skeleton was constructed by way of two radical coupling reactions. These analogues as well as 1a and 1b synthesized previously were tested for their antileishmanial effect in vivo and for their inhibitory activity of protein carboxymethylase (protein methylase II). The replacement of the adenine moiety by uracil or dihydrouracil considerably decreases the antiparasitic activity and the affinity for protein methylase II. The synthetic (S)-sinefungin was as active as the natural one. Interestingly, the C-6' epimer 1b was 50% less active in vitro than the natural sinefungin, but both had identical affinities for the target enzyme.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Animals
  • Antiprotozoal Agents / chemical synthesis*
  • Antiprotozoal Agents / pharmacology
  • Kinetics
  • Leishmania donovani / drug effects
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives*

Substances

  • Antiprotozoal Agents
  • Uracil
  • Adenosine
  • sinefungin