Protolichesterinic acid derivatives: α-methylene-γ-lactones as potent dual activators of PPARγ and Nrf2 transcriptional factors

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3819-22. doi: 10.1016/j.bmcl.2014.06.062. Epub 2014 Jun 27.

Abstract

PPARγ and Nrf2 are important transcriptional factors involved in many signaling pathways, especially in the anti-infectious response of macrophages. Compounds bearing a Michael acceptor moiety are well known to activate such transcriptional factors, we thus evaluated the potency of α,β-unsaturated lactones synthesized using fluorous phase organic synthesis. Compounds were first screened for their cytotoxicity in order to select lactones for PPARγ and Nrf2 activation evaluation. Among them, two α-methylene-γ-lactones were identified as potent dual activators of PPARγ and Nrf2 in macrophages.

Keywords: Michael acceptor; Nrf2; PPARγ; Protolichesterinic acid; α-Methylene-γ-lactones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / chemical synthesis
  • 4-Butyrolactone / chemistry
  • 4-Butyrolactone / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Lactones / chemical synthesis
  • Lactones / chemistry
  • Lactones / pharmacology*
  • Macrophages / drug effects*
  • Mice
  • Molecular Structure
  • NF-E2-Related Factor 2 / metabolism*
  • PPAR gamma / metabolism*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Lactones
  • NF-E2-Related Factor 2
  • PPAR gamma
  • protolichesterinic acid
  • 4-Butyrolactone