ABSTRACT
The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ERbeta were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ERbeta, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Estrogen Receptor beta/agonists , Naphthalenes/chemical synthesis , Naphthols/chemical synthesis , Animals , Animals, Genetically Modified , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Estrogen Receptor beta/chemistry , Female , Genistein/chemistry , Humans , Inflammatory Bowel Diseases/drug therapy , Ligands , Male , Models, Molecular , Molecular Conformation , Molecular Mimicry , Molecular Structure , Naphthalenes/chemistry , Naphthalenes/pharmacology , Naphthols/chemistry , Naphthols/pharmacology , Organ Size/drug effects , Rats , Rats, Inbred Lew , Structure-Activity Relationship , Transcription, Genetic/drug effects , Uterus/anatomy & histology , Uterus/drug effectsABSTRACT
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).
Subject(s)
Estrogen Receptor beta/agonists , Estrogen Receptor beta/antagonists & inhibitors , Oximes/chemical synthesis , Oximes/pharmacology , Binding, Competitive , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Cell Line, Tumor , Estrogen Receptor alpha/agonists , Estrogen Receptor alpha/antagonists & inhibitors , Gene Expression Regulation/genetics , Humans , Keratins/genetics , Ligands , Molecular Conformation , Molecular Structure , Oximes/chemistry , Quantitative Structure-Activity Relationship , RNA, Messenger/analysis , Radioligand AssayABSTRACT
The synthesis and structure-activity relationships of a series of simple biphenyls is described. Optimization of the 4-hydroxy-biphenyl template led to compounds with ERbeta selectivity on the order of 20-70-fold.
