Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta.
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 ERbeta-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 ERbeta over ERalpha. Moreover, in transcription assays, it proved to be a selective and potent ERbeta-full agonist with an EC(50) of 4.8 nM.
Minutolo
Filippo
F
Dipartimento di Scienze Farmaceutiche, Universita di Pisa, Via Bonanno 6, 56126 Pisa, Italy. minutolo@farm.unipi.it
Bertini
Simone
S
Granchi
Carlotta
C
Marchitiello
Teresa
T
Prota
Giovanni
G
Rapposelli
Simona
S
Tuccinardi
Tiziano
T
Martinelli
Adriano
A
Gunther
Jillian R
JR
Carlson
Kathryn E
KE
Katzenellenbogen
John A
JA
Macchia
Marco
M
D003198:Computer Simulation; D016889:Endometrial Neoplasms; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D010091:Oximes; C005704:salicylaldoxime