New scaffolds for the design of selective estrogen receptor modulators.
In the present work we report the synthesis of four new ER ligands which can be used as scaffolds for the introduction of the basic side chains necessary for antiestrogenic activity. Affinities and agonist/antagonist characterization of the ligands for both ERalpha and ERbeta have been determined in a competitive radioligand assay, and in an in vitro coactivator recruitment functional assay, respectively. Molecular modelling techniques have been used in order to rationalize the experimental results. Compound is reported as a novel ERbeta-agonist/ERalpha-antagonist. Two compounds show an interesting antitumour profile towards two pancreatic cancer cell lines and have been selected for in vivo assays.
Martín-Santamaría
Sonsoles
S
Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, 28668-Boadilla del Monte, Madrid, Spain.
Rodríguez
José-Juan
JJ
de Pascual-Teresa
Sonia
S
Gordon
Sandra
S
Bengtsson
Martin
M
Garrido-Laguna
Ignacio
I
Rubio-Viqueira
Belén
B
López-Casas
Pedro P
PP
Hidalgo
Manuel
M
de Pascual-Teresa
Beatriz
B
Ramos
Ana
A
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol