2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole is a ligand and shows species-specific partial agonism of the aryl hydrocarbon receptor

Toxicol Appl Pharmacol. 2009 May 15;237(1):102-10. doi: 10.1016/j.taap.2009.02.015. Epub 2009 Mar 2.


2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and related compounds are a series of anti-cancer candidate pharmaceuticals, that have been shown to activate the AhR. We show that these compounds are high-affinity ligands for the rat AhR, but a quantitative assay for their ability to induce CYP1A1 RNA in H4IIEC3 cells, a measure of activation of the AhR, showed a poor relationship between affinity for the AhR and ability to induce CYP1A1 RNA. 5F 203, an agonist with low potency, was able to antagonise the induction of CYP1A1 RNA by TCDD, while IH 445, a potent agonist, did not antagonise the induction of CYP1A1 RNA by TCDD, and Schild analysis confirmed 5F 203 to be a potent antagonist of the induction of CYP1A1 RNA by TCDD in H4IIEC3 cells. In contrast, several benzothiazoles show potent induction of CYP1A1 RNA in human MCF-7 cells, and 5F 203 is unable to detectably antagonise the induction of CYP1A1 RNA in MCF-7 cells, showing a species difference in antagonism. Evaluation of the anti-proliferative activity of benzothiazoles showed that the ability to agonise the AhR correlated with growth inhibition both in H4IIEC3 cells for a variety of benzothiazoles, and between H4IIEC3 and MCF-7 cells for 5F 203, suggesting an important role of agonism of the AhR in the anti-proliferative activity of benzothiazoles.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / drug effects
  • Actins / genetics
  • Actins / metabolism
  • Analysis of Variance
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzothiazoles / pharmacology*
  • Cell Line, Tumor
  • Cytochrome P-450 CYP1A1 / drug effects*
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1A1 / metabolism
  • Enzyme Induction / drug effects
  • Humans
  • Male
  • RNA, Messenger / analysis
  • Rats
  • Rats, Wistar
  • Receptors, Aryl Hydrocarbon / agonists*
  • Receptors, Aryl Hydrocarbon / metabolism
  • Species Specificity
  • Statistics, Nonparametric
  • Thiazoles / pharmacology*


  • 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole
  • Actins
  • Antineoplastic Agents
  • Benzothiazoles
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Thiazoles
  • Cytochrome P-450 CYP1A1