β-Naphthoflavone analogs as potent and soluble aryl hydrocarbon receptor agonists: Improvement of solubility by disruption of molecular planarity

Yuji Fujita, Mitsuhiro Yonehara, Masashi Tetsuhashi, Tomomi Noguchi-Yachide, Yuichi Hashimoto, Minoru Ishikawa

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The physiological role of aryl hydrocarbon receptor (AhR) is not yet fully understood, and investigation is hampered by the limited solubility of reported AhR ligands in aqueous media. To achieve improved solubility, we focused on our previous finding that planarity-disruption of molecules leads to less efficient crystal packing and greater aqueous solubility. Here, we describe chemical modification of an AhR agonist, β-naphthoflavone, focusing on planarity-disruption. As expected, introduction of substituents at the ortho-positions of the phenyl group resulted in greater solubility. Among the compounds prepared, the fluoro analog showed more potent AhR agonistic activity and greater solubility than did β-naphthoflavone. Our results indicate that this strategy to improve aqueous solubility, that is, introduction of substituent(s) that disrupt planarity, may be generally applicable to bicyclic molecules.

Original languageEnglish
Pages (from-to)1194-1203
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number3
DOIs
Publication statusPublished - 2010 Feb 1
Externally publishedYes

Keywords

  • AhR agonist
  • Naphthoflavone
  • Solubility

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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