ERbeta ligands. Part 2: Synthesis and structure-activity relationships of a series of 4-hydroxy-biphenyl-carbaldehyde oxime derivatives.
A series of biphenyl carbaldehyde oximes (6) was prepared and shown to have significant selectivity for the estrogen receptor-beta (ERbeta). The exploitation of the oxime moiety as a hydrogen bond donating group, which mimicked the C-ring of genistein makes these compounds unique. Molecular modeling studies showed the oxime moiety hydrogen bonding to the histidine residue, which was supported by the structure-activity relationships. The most potent compounds in this study had IC50 values in a radioligand binding assay of between 8-35 nM. Among the most selective compounds were 6i and 6s (49- and 31-fold ERbeta selective, respectively).
Yang
Cuijian
C
Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
Edsall
Richard
R
Harris
Heather A
HA
Zhang
Xiaochun
X
Manas
Eric S
ES
Mewshaw
Richard E
RE
D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007633:Keratins / Q000235:genetics; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012333:RNA, Messenger / Q000032:analysis; D011869:Radioligand Assay
C493771:4-hydroxy-biphenyl-carbaldehyde oxime; D001713:Biphenyl Compounds; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D010091:Oximes; D012333:RNA, Messenger; D007633:Keratins