beta-Naphthoflavone analogs as potent and soluble aryl hydrocarbon receptor agonists: improvement of solubility by disruption of molecular planarity.

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Fujita Y, Yonehara M, Tetsuhashi M, Noguchi-Yachide T, Hashimoto Y, Ishikawa M

beta-Naphthoflavone analogs as potent and soluble aryl hydrocarbon receptor agonists: improvement of solubility by disruption of molecular planarity.

Bioorg Med Chem. 2010 Feb;18(3):1194-203. doi: 10.1016/j.bmc.2009.12.036. Epub 2009 Dec 21.

PubMed ID

20060304 [ View in PubMed

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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, beta-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 beta-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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
beta-Naphthoflavone	Aryl hydrocarbon receptor	EC 50 (nM)	1400	N/A	N/A	Details