Synthesis and biological evaluation of dihydroeptastatin, a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase

  • J Med Chem. 1992 Sep 4;35(18):3388-93. doi: 10.1021/jm00096a015.
E A Bone  1 ,  A H Davidson ,  C N Lewis ,  R S Todd
Affiliations
  • 1. Department of Medicinal Chemistry, British Bio-technology Limited, Cowley, Oxford, U.K.
PMID: 1527791 DOI: 10.1021/jm00096a015
Abstract

The total synthesis of the novel hydroxylated HMG-CoA reductase inhibitor dihydroeptastatin (7) is described. The key C-3 hydroxyl group is introduced via a Baeyer-Villiger reaction on the methyl ketone 17 which is obtained in three high-yielding steps from the known tricyclic lactone 12. In an isolated enzyme assay dihydroeptastatin had a similar IC50 to mevinolin but in cellular assays using Hep G2 and HES 9 cell lines, dihydroeptastatin was much less potent. No selectivity between the two cell lines was observed.