Steroidomimetic aminomethyl spiroacetals as novel inhibitors of the enzyme Δ8,7-sterol isomerase in cholesterol biosynthesis

Arch Pharm (Weinheim). 2014 Feb;347(2):108-22. doi: 10.1002/ardp.201300296. Epub 2013 Dec 4.

Abstract

Grundmann's ketone is converted to a spiroacetal containing a 5-hydroxymethyl-5-nitro-1,3-dioxane moiety whose hydroxymethyl group can be esterified or directly substituted with primary and secondary amines. Among the resulting aminomethyl spiroacetals, several ones bearing diamino residues were found to be inhibitors of the enzyme Δ8,7-isomerase in cholesterol biosynthesis. The complex bicyclic building block derived from Grundmann's ketone could be replaced by a properly substituted tetraline scaffold, without noteworthy loss in activity. This opens the opportunity to perform further structural modifications for the design of new steroidomimetic inhibitors of human Δ8,7-isomerase.

Keywords: Acetal; Cholesterol biosynthesis; Enzyme inhibitors; Isomerase; Steroidomimetic.

MeSH terms

  • Acetals / chemical synthesis*
  • Acetals / pharmacology*
  • Acetals / toxicity
  • Anticholesteremic Agents / chemical synthesis*
  • Anticholesteremic Agents / pharmacology*
  • Anticholesteremic Agents / toxicity
  • Cell Survival
  • Cholesterol / biosynthesis*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • HL-60 Cells
  • Humans
  • Inhibitory Concentration 50
  • Molecular Mimicry
  • Molecular Structure
  • Steroid Isomerases / antagonists & inhibitors*
  • Steroid Isomerases / metabolism
  • Structure-Activity Relationship

Substances

  • Acetals
  • Anticholesteremic Agents
  • Enzyme Inhibitors
  • Cholesterol
  • Steroid Isomerases
  • delta(8)-delta(7)-sterol isomerase
  • EBP protein, human