TY - JOUR
T1 - Acyclic amides as estrogen receptor ligands
T2 - Synthesis, binding, activity and receptor interaction
AU - Stauffer, Shaun R.
AU - Sun, Jun
AU - Katzenellenbogen, Benita S.
AU - Katzenellenbogen, John A.
N1 - We are grateful for support of this research through grants from the US Army Breast Cancer Research Program (DAMD17-97-1-7076) and the National Institutes of Health (HHS 5R37 DK15556 and CA18119). We thank Kathryn E. Carlson for performing binding assays and Scott Wilson, Richard Cesati and Professor Greg Girolami for valuable assistance with X-ray data acquisition, structure determination and refinement. 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 - 2000/6
Y1 - 2000/6
N2 - We have prepared a series of bisphenolic amides that mimic bibenzyl and homobibenzyl motifs commonly found as substructures in ligands for the estrogen receptor (ER). Representative members were prepared from three classes: N-phenyl benzamides, N-phenyl acetamides, and N-benzyl benzamides; in some cases the corresponding thiocarboxamides and sulfonamides were also prepared. Of these three classes, the N-phenyl benzamides had the highest affinity for ER, the N-phenyl acetamides had lower, and the N-benzyl benzamides were prone to fragmentation via a quinone methide intermediate. In the N-phenyl benzamide series, the highest affinity analogues had bulky N-substituents; a CF3 group, in particular, conferred high affinity. The thiocarboxamides bound better than the corresponding carboxamides and these bound better than the corresponding sulfonamides. Binding affinity comparisons suggest that the p-hydroxy group on the benzoate ring, which contributes most to the binding, is playing the role of the phenolic hydroxyl of estradiol. Computational studies and NMR and X-ray crystallographic analysis indicate that the two anilide systems studied have a strong preference for the s-cis or exo amide conformation, which places the two aromatic rings in a syn orientation. We used this structural template, together with the X-ray structure of the ER ligand binding domain, to elaborate an additional hydrogen bonding site on a benzamide system that elevated receptor binding further. When assayed on the individual ER subtypes, ERα and ERβ, these compounds show modest binding affinity preference for ERα. In a reporter gene transfection assay of transcriptional activity, the amides generally have full to nearly full agonist character on ERα, but have moderate to full antagonist character on ERβ. One high affinity carboxamide is 500-fold more potent as an agonist on ERα than on ERβ. This work illustrates that ER ligands having simple amide core structures can be readily prepared, but that high affinity binding requires an appropriate distribution of bulk, polarity, and functionality. The strong conformational preference of the core anilide function in all of these ligands defines a rather rigid geometry for further structural and functional expansion of these series. Copyright (C) 2000 Elsevier Science Ltd.
AB - We have prepared a series of bisphenolic amides that mimic bibenzyl and homobibenzyl motifs commonly found as substructures in ligands for the estrogen receptor (ER). Representative members were prepared from three classes: N-phenyl benzamides, N-phenyl acetamides, and N-benzyl benzamides; in some cases the corresponding thiocarboxamides and sulfonamides were also prepared. Of these three classes, the N-phenyl benzamides had the highest affinity for ER, the N-phenyl acetamides had lower, and the N-benzyl benzamides were prone to fragmentation via a quinone methide intermediate. In the N-phenyl benzamide series, the highest affinity analogues had bulky N-substituents; a CF3 group, in particular, conferred high affinity. The thiocarboxamides bound better than the corresponding carboxamides and these bound better than the corresponding sulfonamides. Binding affinity comparisons suggest that the p-hydroxy group on the benzoate ring, which contributes most to the binding, is playing the role of the phenolic hydroxyl of estradiol. Computational studies and NMR and X-ray crystallographic analysis indicate that the two anilide systems studied have a strong preference for the s-cis or exo amide conformation, which places the two aromatic rings in a syn orientation. We used this structural template, together with the X-ray structure of the ER ligand binding domain, to elaborate an additional hydrogen bonding site on a benzamide system that elevated receptor binding further. When assayed on the individual ER subtypes, ERα and ERβ, these compounds show modest binding affinity preference for ERα. In a reporter gene transfection assay of transcriptional activity, the amides generally have full to nearly full agonist character on ERα, but have moderate to full antagonist character on ERβ. One high affinity carboxamide is 500-fold more potent as an agonist on ERα than on ERβ. This work illustrates that ER ligands having simple amide core structures can be readily prepared, but that high affinity binding requires an appropriate distribution of bulk, polarity, and functionality. The strong conformational preference of the core anilide function in all of these ligands defines a rather rigid geometry for further structural and functional expansion of these series. Copyright (C) 2000 Elsevier Science Ltd.
UR - http://www.scopus.com/inward/record.url?scp=0034086636&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034086636&partnerID=8YFLogxK
U2 - 10.1016/S0968-0896(00)00075-4
DO - 10.1016/S0968-0896(00)00075-4
M3 - Article
C2 - 10896109
AN - SCOPUS:0034086636
SN - 0968-0896
VL - 8
SP - 1293
EP - 1316
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 6
ER -