Synthesis of a novel cyclic prodrug of S-allyl-glutathione able to attenuate LPS-induced ROS production through the inhibition of MAPK pathways in U937 cells

Mol Pharm. 2015 Jan 5;12(1):66-74. doi: 10.1021/mp500431r. Epub 2014 Nov 19.

Abstract

A novel cyclic prodrug of S-allyl-glutathione (CP11), obtained by using an acyloxy-alkoxy linker, was estimated for its pharmacokinetic and biological properties. The stability of CP11 was evaluated at pH 1.2, 7.4, in simulated fluids with different concentrations of enzymes, and in human plasma. The anti-inflammatory ability of CP11 was assessed in U937 cells, an immortalized human monocyte cell line. Results showed that CP11 is stable at acidic pH showing a possible advantage for oral delivery due to the longer permanence in the stomach. Having a permeability coefficient of 2.49 × 10(-6) cm s(-1), it was classified as discrete BBB-permeable compound. Biological studies revealed that CP11 is able to modulate inflammation mediated by LPS in U937 cells preventing the increase of ROS intracellular levels through interaction with the MAPK pathway.

Keywords: MAPK pathway; acyloxy-alkoxy linker; cyclic prodrug; glutathione.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane Permeability
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Glutathione / chemical synthesis*
  • Glutathione / chemistry*
  • Humans
  • Hydrogen-Ion Concentration
  • Lipopolysaccharides / chemistry
  • MAP Kinase Signaling System / drug effects*
  • Models, Chemical
  • Monocytes / cytology
  • Permeability
  • Prodrugs / chemistry*
  • Reactive Oxygen Species / metabolism*
  • Temperature
  • U937 Cells

Substances

  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Prodrugs
  • Reactive Oxygen Species
  • Glutathione