Design, synthesis and biological study of pinacolyl boronate-substituted stilbenes as novel lipogenic inhibitors

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5638-41. doi: 10.1016/j.bmcl.2011.05.124. Epub 2011 Jun 28.

Abstract

A pilot library of novel 4,4,5,5-tetramethyl-2-(4-substitutedstyrylphenyl)-1,3,2 dioxaborolane derivatives has been synthesized. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboratophenyl)-methyl triphenylphosphonium bromide 3 was treated with various aldehydes in the presence of 3 equiv of (t)BuONa in DMF, and stirred at room temperature for 4-6h to yield the corresponding boron-containing stilbene derivatives in 71-94% yields. Several of them, including BF102 and BF175, have the lipogenesis inhibitory effect by suppressing lipogenic gene expression in mammalian hepatocytes. Further, BF102 also inhibits cholesterol biosynthesis by suppressing HMG-CoA reductase gene expression in hepatocytes. Interestingly, our preliminary in vivo data suggests that BF102 has no significant toxicity in mice at the highest possible dose we can administered. Thus, BF102 is a potential lead for the next generation of lipid-lowering drugs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Boronic Acids / chemical synthesis
  • Boronic Acids / chemistry
  • Boronic Acids / pharmacology*
  • Cell Line
  • Chemistry Techniques, Synthetic
  • Cholesterol / biosynthesis
  • Cholesterol / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Fatty Acid Synthases / antagonists & inhibitors*
  • Fatty Acid Synthases / genetics
  • Fatty Acid Synthases / metabolism
  • Gene Expression Profiling
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Lipogenesis / drug effects*
  • Lipogenesis / genetics
  • Mice
  • Molecular Structure
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Small Molecule Libraries
  • Stereoisomerism
  • Stilbenes / chemical synthesis
  • Stilbenes / chemistry
  • Stilbenes / pharmacology*
  • Structure-Activity Relationship

Substances

  • BF175 compound
  • Boronic Acids
  • Enzyme Inhibitors
  • RNA, Messenger
  • Small Molecule Libraries
  • Stilbenes
  • Cholesterol
  • Hydroxymethylglutaryl CoA Reductases
  • Fatty Acid Synthases