Investigations on the influence of terminal groups at the C2-propyl side chain of 1,1-bis(4-hydroxyphenyl)-2-phenylpent-1-ene and 1,1,2-tris(4-hydroxyphenyl)pent-1-ene on the estrogen receptor binding and the estrogenic/anti-estrogenic properties.
1,1-bis(4-Hydroxyphenyl)-2-phenylpent-1-ene (5) and 1,1,2-tris(4-hydroxyphenyl)pent-1-ene (6) derivatives with terminal CN (5a, 6a), NH(2) (5b, 6b), NHCOCH(3) (5c, 6c), NHCOC(2)H(5) (5d, 6d) groups at the C2-propyl chain were synthesized and assayed in vitro for estrogen receptor (ER) binding affinity (RBA) in a competition experiment with [3H]estradiol and for estrogenic and anti-estrogenic properties in a luciferase assay with ER-positive MCF-7-2a cells, stably transfected with the plasmid ERE(wtc)luc. The CN as well as the NH(2) group reduced the RBA-values (5: 2.09%; 5a: 1.50%; 5b: 0.07%; 6: 4.03%; 6a: 0.67%; 6b: 0.20%) and the antagonistic potency (5: IC(50)=0.05 microM; 5a: IC(50)=0.43 microM; 5b: IC(50)=1.50 microM; 6: IC(50)=0.07 microM; 6a: IC(50)=0.60 microM; 6b: IC(50)=2.00 microM). Derivatization of the amino function with acetic anhydride and propionic anhydride did not change the RBA-value but altered the antagonistic profile (5c: IC(50)=2.50 microM; 5d: IC(50)=not detectable; 6c: IC(50)=0.65 microM; 6d: IC(50)=1.00 microM). Agonistic effects were only detected for the amine 6b (34.2% activation of the luciferase expression). These data document that estrogen receptor binding and the antagonistic effects can be modified by terminal groups at the C2-propyl chain of the pure antagonists 5 and 6. The mode of action is unclear. However, it can be assumed that the elongation of the side chain causes a reorientation in the LBD in order to locate the side chain in a side pocket near the ligand binding domain.
Gust
Ronald
R
Institute of Pharmacy, Free University of Berlin, Königin-Luise Strasse 2+4, D-14195, Berlin, Germany. rgust@zedat.fu-berlin.de
Lubczyk
Veronika
V
D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000475:Alkenes; D020847:Estrogen Receptor Modulators; D008024:Ligands; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; D008156:Luciferases