TY - JOUR
T1 - Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor β
AU - Minutolo, Filippo
AU - Bertini, Simone
AU - Granchi, Carlotta
AU - Marchitiello, Teresa
AU - Prota, Giovanni
AU - Rapposelli, Simona
AU - Tuccinardi, Tiziano
AU - Martinelli, Adriano
AU - Gunther, Jillian R.
AU - Carlson, Kathryn E.
AU - Katzenellenbogen, John A.
AU - Macchia, Marco
PY - 2009/2/12
Y1 - 2009/2/12
N2 - The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of nonsteroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected molecules belonging to the monoaryl-salicylaldoxime chemical class in an attempt to improve further their ERβ-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compound showed the best affinity (K i = 7.1 nM) and selectivity for ERβ over ERa. Moreover, in transcription assays, it proved to be a selective and potent ERS-full agonist with an EC 50 of 4.8 nM.
AB - The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of nonsteroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected molecules belonging to the monoaryl-salicylaldoxime chemical class in an attempt to improve further their ERβ-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compound showed the best affinity (K i = 7.1 nM) and selectivity for ERβ over ERa. Moreover, in transcription assays, it proved to be a selective and potent ERS-full agonist with an EC 50 of 4.8 nM.
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U2 - 10.1021/jm801458t
DO - 10.1021/jm801458t
M3 - Article
C2 - 19128016
AN - SCOPUS:61449153994
SN - 0022-2623
VL - 52
SP - 858
EP - 867
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -