New diphenylmethane derivatives as peroxisome proliferator-activated receptor alpha/gamma dual agonists endowed with anti-proliferative effects and mitochondrial activity

Eur J Med Chem. 2017 Feb 15;127:379-397. doi: 10.1016/j.ejmech.2016.12.047. Epub 2016 Dec 24.


We screened a short series of new chiral diphenylmethane derivatives and identified potent dual PPARα/γ partial agonists. As both enantiomers of the most active compound 1 displayed an unexpected similar transactivation activity, we performed docking experiments to provide a molecular understanding of their similar partial agonism. We also evaluated the ability of both enantiomers of 1 and racemic 2 to inhibit colorectal cancer cells proliferation: (S)-1 displayed a more robust activity due, at least in part, to a partial inhibition of the Wnt/β-catenin signalling pathway that is upregulated in the majority of colorectal cancers. Finally, we investigated the effects of (R)-1, (S)-1 and (R,S)-2 on mitochondrial function and demonstrated that they activate the carnitine shuttle system through upregulation of carnitine/acylcarnitine carrier (CAC) and carnitine-palmitoyl-transferase 1 (CPT1) genes. Consistent with the notion that these are PPARα target genes, we tested and found that PPARα itself is regulated by a positive loop. Moreover, these compounds induced a significant mitochondrial biogenesis. In conclusion, we identified a new series of dual PPARα/γ agonists endowed with novel anti-proliferative properties associated with a strong activation of mitochondrial functions and biogenesis, a potential therapeutic target of the treatment of insulin resistance.

Keywords: Anti-proliferative effects; Docking experiments; Gene expression analysis; Mitochondrial biogenesis; PPAR.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Benzhydryl Compounds / chemical synthesis
  • Benzhydryl Compounds / chemistry*
  • Benzhydryl Compounds / metabolism
  • Benzhydryl Compounds / pharmacology*
  • Carnitine / metabolism
  • Cell Proliferation / drug effects
  • Drug Evaluation, Preclinical
  • HT29 Cells
  • Hep G2 Cells
  • Humans
  • Insulin Resistance
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Molecular Docking Simulation
  • PPAR alpha / agonists*
  • PPAR alpha / chemistry
  • PPAR alpha / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / chemistry
  • PPAR gamma / metabolism
  • Protein Conformation
  • Signal Transduction / drug effects
  • beta Catenin / metabolism


  • Antineoplastic Agents
  • Benzhydryl Compounds
  • PPAR alpha
  • PPAR gamma
  • beta Catenin
  • diphenylmethane
  • Carnitine