TY - JOUR
T1 - Estrogen pyrazoles
T2 - Defining the pyrazole core structure and the orientation of substituents in the ligand binding pocket of the estrogen receptor
AU - Stauffer, Shaun R.
AU - Huang, Ying
AU - Coletta, Christopher J.
AU - Tedesco, Rosanna
AU - Katzenellenbogen, John A.
N1 - Funding Information:
We are grateful for support of this research through grants from the US Army Breast Cancer Research Program (DAMD17-97-7076) and the National Institutes of Health (PHS 5R37 DK15556 and T32 CA 09067 (Training Grant for Y. H.)). We thank Kathryn E. Carlson for performing binding assays and for helpful comments. 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 Institutes of Health (RR 01575), and the National Science Foundation (PCM 8121494).
PY - 2001
Y1 - 2001
N2 - Previously, we reported that certain tetrasubstituted 1,3,5-triaryl-4-alkyl-pyrazoles bind to the estrogen receptor (ER) with high affinity (Fink, B. E.; Mortenson, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205-219; Stauffer, S. R.; Katzenellenbogen, J. A. J. Comb. Chem. 2000, 2, 318-329; Stauffer, S. R.; Coletta, C. J.; Sun, J.; Tedesco, R.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). To investigate how cyclic permutation of the two nitrogen atoms of a pyrazole might affect ER binding affinity, we prepared a new pyrazole core isomer, namely a 1,3,4-triaryl-5-alkyl-pyrazole (2), to compare it with our original pyrazole (1). We also prepared several peripherally matched core pyrazole isomer sets to investigate whether the two pyrazole series share a common binding orientation. Our efficient, regioselective synthetic route to these pyrazoles relies on the acylation of a hydrazone anion, followed by cyclization, halogenation, and Suzuki coupling. We found that the ER accommodates 1,3,4-triaryl-pyrazoles of the isomeric series only somewhat less well than the original 1,3,5-triaryl series, and it appears that both series share a common binding mode. This preferred orientation for the 1,3,5-triaryl-4-alkyl-pyrazoles is supported by binding affinity measurements of analogues in which the phenolic hydroxyl groups were systematically removed from each of the three aryl groups, and the orientation is consistent, as well, with molecular modeling studies. These studies provide additional insight into the design of heterocyclic core structures for the development of high affinity ER ligands by combinatorial methods.
AB - Previously, we reported that certain tetrasubstituted 1,3,5-triaryl-4-alkyl-pyrazoles bind to the estrogen receptor (ER) with high affinity (Fink, B. E.; Mortenson, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205-219; Stauffer, S. R.; Katzenellenbogen, J. A. J. Comb. Chem. 2000, 2, 318-329; Stauffer, S. R.; Coletta, C. J.; Sun, J.; Tedesco, R.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). To investigate how cyclic permutation of the two nitrogen atoms of a pyrazole might affect ER binding affinity, we prepared a new pyrazole core isomer, namely a 1,3,4-triaryl-5-alkyl-pyrazole (2), to compare it with our original pyrazole (1). We also prepared several peripherally matched core pyrazole isomer sets to investigate whether the two pyrazole series share a common binding orientation. Our efficient, regioselective synthetic route to these pyrazoles relies on the acylation of a hydrazone anion, followed by cyclization, halogenation, and Suzuki coupling. We found that the ER accommodates 1,3,4-triaryl-pyrazoles of the isomeric series only somewhat less well than the original 1,3,5-triaryl series, and it appears that both series share a common binding mode. This preferred orientation for the 1,3,5-triaryl-4-alkyl-pyrazoles is supported by binding affinity measurements of analogues in which the phenolic hydroxyl groups were systematically removed from each of the three aryl groups, and the orientation is consistent, as well, with molecular modeling studies. These studies provide additional insight into the design of heterocyclic core structures for the development of high affinity ER ligands by combinatorial methods.
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U2 - 10.1016/S0968-0896(00)00228-5
DO - 10.1016/S0968-0896(00)00228-5
M3 - Article
C2 - 11197334
AN - SCOPUS:0035189954
SN - 0968-0896
VL - 9
SP - 141
EP - 150
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 1
ER -