Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2473-6. doi: 10.1016/j.bmcl.2014.04.013. Epub 2014 Apr 13.

Abstract

Bis-aryloxadiazoles are common scaffolds in medicinal chemistry due to their wide range of biological activities. Previously, we identified a 1,2,4-bis-aryloxadiazole that blocks mammary branching morphogenesis through activation of the aryl hydrocarbon receptor (AHR). In addition to defects in mammary differentiation, AHR stimulation induces toxicity in many other tissues. We performed a structure activity relationship (SAR) study of 1,2,4-bis-aryloxadiazole to determine which moieties of the molecule are critical for AHR activation. We validated our results with a functional biological assay, using desmosome formation during mammary morphogenesis to indicate AHR activity. These findings will aid the design of oxadiazole derivative therapeutics with reduced off-target toxicity profiles.

Keywords: Aryl hydrocarbon receptor; Branching morphogenesis; Dioxin; Mammary gland; Oxadiazole.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Structure-Activity Relationship

Substances

  • Oxadiazoles
  • Receptors, Aryl Hydrocarbon