Optimizing of 2,3-diarylindenes as fluorescent estrogens: variation of the acceptor group, ortho substitution of the 2-ring, and C-1 methylation.
In an attempt to elucidate steric and electronic factors that affect the fluorescence and estrogen receptor binding properties of 2,3-diarylindenes, we have prepared and examined the behavior of 11 analogues bearing substituents on the 1-position or on the 2-aryl ring. These compounds were synthesized by alkylation of a 1,2-diarylethanone with 3-methoxybenzyl chloride, followed by cyclodehydration to the indene. The electronic spectra of those compounds without tau-electron accepting groups on the 2-aryl ring display the absorbance and fluorescence of a hindered stilbene system; those with nitro and cyano substituents on the 2-aryl ring show charge-transfer character, having a more bathochromic absorption and fluorescence. One bisphenolic nitroindene, in particular, shows a strong, long-wavelength absorption and an intense emission, with a large Stokes' shift that is highly sensitive to solvent polarity. Estrogen receptor binding affinity measurements on these compounds indicate that substituents that twist the pendant aryl rings (such as a 1-methyl group, or an o-methyl or trifluoromethyl group on the 2-phenyl ring) increase binding affinity. Bulky (4-bromo) or electron-withdrawing groups (3- and 4-nitro, 4-cyano) on the 2-phenyl group, or its replacement with a 3-pyridyl group, greatly reduce binding affinity, suggesting that the complementary region of the receptor is relatively intolerant of bulk and may have specific hydrogen-bonding requirements. This investigation of the concurrent effects of substituents on the fluorescence properties and receptor binding affinity of 2,3-diarylindenes should assist in the development of effective, inherently fluorescent ligands for the estrogen receptor.
Anstead
G M
GM
Department of Chemistry, University of Illinois, St., Urbana 61801.
Katzenellenbogen
J A
JA
D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D004563:Electrochemistry; D005456:Fluorescent Dyes; D006900:Hydroxylation; D007192:Indenes / Q000138:chemical synthesis / Q000378:metabolism*; D008745:Methylation; D011960:Receptors, Estrogen / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013053:Spectrophotometry; D013329:Structure-Activity Relationship
D005456:Fluorescent Dyes; D007192:Indenes; D011960:Receptors, Estrogen