TY - JOUR
T1 - Triarylethylene bisphenols with a novel cycle are ligands for the estrogen receptor
AU - Kim, Sung Hoon
AU - Katzenellenbogen, John A.
N1 - Funding Information:
We are grateful for support of this research through a grant from the National Institutes of Health. We thank Kathryn E. Carlson for performing the receptor binding studies and Marvin J. Meyers for assistance with the preparation of Figure 2 . NMR spectra were obtained in the Varian Oxford Instrument Center for Excellence in NMR Laboratory. Funding for this instrumentation was provided in part from the W. M. Keck Foundation and the National Science Foundation (NSF CHE 96-10502). Mass spectra were obtained on instruments supported by grants from the National Institute of General Medical Sciences (GM 27029), the National Institute of Health (RR 01575), and the National Science Foundation (PCM 8121494).
PY - 2000/4
Y1 - 2000/4
N2 - We have prepared a series of triarylethylene and triarylethane systems, analogues of the selective antiestrogen tamoxifen, in which the alkyl substituent is tethered to the distal, rather than the proximal aryl ring by a 5-, 6-, or 7-membered carbocycle. This unusual cyclic structure rigidifies the ligand and adds bulk in a manner that is different from the more typical cyclization to the proximal aryl ring, as in the antiestrogen nafoxidine. These new systems were prepared efficiently by the addition of a benzylic sodium reagent, generated from the corresponding chloride by treatment with sodium naphthalenide, to a doubly protected 4,4'-dihydroxybenzophenone, followed by dehydration and deprotection. In all cases, formation of the exocyclic alkene was preferred. Two of the corresponding alkanes could be obtained by catalytic hydrogenation. All of these compounds have relatively high binding affinity for the estrogen receptor, and some of them demonstrate a significant level of affinity selectivity for the estrogen receptor alpha subtype. Accommodation of these newly rigidified cyclic triarylethylene systems into the ligand-binding pocket of the estrogen receptor can be visualized by molecular modeling. (C) 2000 Elsevier Science Ltd.
AB - We have prepared a series of triarylethylene and triarylethane systems, analogues of the selective antiestrogen tamoxifen, in which the alkyl substituent is tethered to the distal, rather than the proximal aryl ring by a 5-, 6-, or 7-membered carbocycle. This unusual cyclic structure rigidifies the ligand and adds bulk in a manner that is different from the more typical cyclization to the proximal aryl ring, as in the antiestrogen nafoxidine. These new systems were prepared efficiently by the addition of a benzylic sodium reagent, generated from the corresponding chloride by treatment with sodium naphthalenide, to a doubly protected 4,4'-dihydroxybenzophenone, followed by dehydration and deprotection. In all cases, formation of the exocyclic alkene was preferred. Two of the corresponding alkanes could be obtained by catalytic hydrogenation. All of these compounds have relatively high binding affinity for the estrogen receptor, and some of them demonstrate a significant level of affinity selectivity for the estrogen receptor alpha subtype. Accommodation of these newly rigidified cyclic triarylethylene systems into the ligand-binding pocket of the estrogen receptor can be visualized by molecular modeling. (C) 2000 Elsevier Science Ltd.
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U2 - 10.1016/S0968-0896(00)00016-X
DO - 10.1016/S0968-0896(00)00016-X
M3 - Article
C2 - 10819167
AN - SCOPUS:0034067895
SN - 0968-0896
VL - 8
SP - 785
EP - 793
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 4
ER -