Design, synthesis and biological evaluation of hydroxamic acid derivatives as potential high density lipoprotein (HDL) receptor CLA-1 up-regulating agents

Molecules. 2011 Nov 2;16(11):9178-93. doi: 10.3390/molecules16119178.

Abstract

Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) were reported in our recent publication as novel human high density lipoprotein (HDL) receptor CD36 and Lysosomal integral membrane protein-II Analogous-1 (CLA-1) up-regulators. As part of a broader effort to more fully explore the structure-activity relationships (SAR) of CLA-1 up-regulators, we synthesized a series of hydroxamic acid derivatives and evaluated their CLA-1 up-regulating activities in HepG2 cells. Some compounds exhibited over 10-fold up-regulation of CLA-1 expression in HepG2 cells at 10 μg/mL concentration. The compound 1g showed the best potency, with a lower EC(50) than TSA (EC(50) = 0.32 μM versus 1.2 μM). These compounds provide early new CLA-1 up-regulators with potential for treating atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / drug therapy
  • Dose-Response Relationship, Drug
  • Hep G2 Cells
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / therapeutic use
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry*
  • Hydroxamic Acids / metabolism
  • Hydroxamic Acids / therapeutic use
  • Lipoproteins, HDL / metabolism
  • Mice
  • Molecular Structure
  • Scavenger Receptors, Class B / metabolism*
  • Structure-Activity Relationship
  • Up-Regulation
  • Vorinostat

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Lipoproteins, HDL
  • SCARB1 protein, human
  • Scavenger Receptors, Class B
  • trichostatin A
  • Vorinostat