TY - JOUR
T1 - Torsionally and Hydrophobically Modified 2,3-Diarylindenes as Estrogen Receptor Ligands
AU - Anstead, Gregory M.
AU - Peterson, Chad S.
AU - Pinney, Kevin G.
AU - Wilson, Scott R.
AU - Katzenellenbogen, John A.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1990/10
Y1 - 1990/10
N2 - 2,3-Diarylindenes are ligands for the estrogen receptor which display intrinsic fluorescence. In order to optimize the receptor binding affinity of these compounds while preserving their desirable fluorescence properties, a series of torsionally modified analogues were prepared. A fluorine or methyl group was introduced on either of the two phenyl substituents ortho to their attachment site to the indene nucleus, in order to increase the out-of-plane twist of the appended rings. The analogues were prepared by the benzylation of appropriate deoxybenzoins, followed by Friedel-Crafts cyclic alkylation-dehydration. Comparison of the X-ray crystal structure of one analogue with unsubstituted analogues confirms the torsional perturbation effected by the ortho substituent The torsional disposition of the C-2 aryl group in the substituted diphenylindenes is further investigated by UV (absorbance maxima and molar absorptivities), fluorescence (Stokes' shift), and NMR (chemical shifts). These spectroscopic measurements indicate increasing twisting between the C-2 aryl substituent and the indene system according to the following order: 3-ring o-Me-indene 9f < diphenylindene 15 = 20° < 3-ring o-F-indene 9c < 1-Me-indene 16 < 2-ring o-F-indene 9b < 2-ring o-Me-indene 9e = 63 °. The binding affinity of these analogues to the estrogen receptor was evaluated by a competitive radiometric receptor binding assay. While o-fluoro or o-methyl substitution on the 3-ring increases binding only slightly, binding of the o-fluoro 2-ring analogue is increased ca. 6-fold and the o-methyl analogue 11-fold, giving, in the latter case, a compound with an affinity equivalent to that of estradiol. The increase in binding affinity afforded by ortho substitution correlates with the increase in the torsion angle of the C-2 aryl ring. A thermodynamic evaluation of the receptor fit (Andrews, P. R.; Craik, D. J.; Martin, J. L. J. Med. Chem. 1984, 27, 1648) indicates that, for the o-methyl 2-ring analogue, the effect of the ortho substitution on increasing receptor binding appears to be a combination of increased surface area due to the substituent itself, together with a change in surface area of the ligand that results from the increased torsion of the two aryl rings. An o-fluoro substituent on the 2-ring provides a compromise between the relative planarity required for high fluorescence intensity and the molecular shape needed for increased estrogen receptor binding affinity. o-Methyl, o-fluoro, and p-methyl substitution of the 3-ring have no value in the development of a fluorescent, higher affinity 2,3-diarylindene.
AB - 2,3-Diarylindenes are ligands for the estrogen receptor which display intrinsic fluorescence. In order to optimize the receptor binding affinity of these compounds while preserving their desirable fluorescence properties, a series of torsionally modified analogues were prepared. A fluorine or methyl group was introduced on either of the two phenyl substituents ortho to their attachment site to the indene nucleus, in order to increase the out-of-plane twist of the appended rings. The analogues were prepared by the benzylation of appropriate deoxybenzoins, followed by Friedel-Crafts cyclic alkylation-dehydration. Comparison of the X-ray crystal structure of one analogue with unsubstituted analogues confirms the torsional perturbation effected by the ortho substituent The torsional disposition of the C-2 aryl group in the substituted diphenylindenes is further investigated by UV (absorbance maxima and molar absorptivities), fluorescence (Stokes' shift), and NMR (chemical shifts). These spectroscopic measurements indicate increasing twisting between the C-2 aryl substituent and the indene system according to the following order: 3-ring o-Me-indene 9f < diphenylindene 15 = 20° < 3-ring o-F-indene 9c < 1-Me-indene 16 < 2-ring o-F-indene 9b < 2-ring o-Me-indene 9e = 63 °. The binding affinity of these analogues to the estrogen receptor was evaluated by a competitive radiometric receptor binding assay. While o-fluoro or o-methyl substitution on the 3-ring increases binding only slightly, binding of the o-fluoro 2-ring analogue is increased ca. 6-fold and the o-methyl analogue 11-fold, giving, in the latter case, a compound with an affinity equivalent to that of estradiol. The increase in binding affinity afforded by ortho substitution correlates with the increase in the torsion angle of the C-2 aryl ring. A thermodynamic evaluation of the receptor fit (Andrews, P. R.; Craik, D. J.; Martin, J. L. J. Med. Chem. 1984, 27, 1648) indicates that, for the o-methyl 2-ring analogue, the effect of the ortho substitution on increasing receptor binding appears to be a combination of increased surface area due to the substituent itself, together with a change in surface area of the ligand that results from the increased torsion of the two aryl rings. An o-fluoro substituent on the 2-ring provides a compromise between the relative planarity required for high fluorescence intensity and the molecular shape needed for increased estrogen receptor binding affinity. o-Methyl, o-fluoro, and p-methyl substitution of the 3-ring have no value in the development of a fluorescent, higher affinity 2,3-diarylindene.
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U2 - 10.1021/jm00172a008
DO - 10.1021/jm00172a008
M3 - Article
C2 - 2213825
AN - SCOPUS:0025082593
SN - 0022-2623
VL - 33
SP - 2726
EP - 2734
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 10
ER -