Design, Synthesis And Biological Evaluation Of Novel Selective Estrogen Receptor Modulators

Estrogens regulate many physiological processes, including normal cell growth, development, and tissue-specific gene regulation in the reproductive tract and in the central nervous and skeletal systems. Estrogens also influence the pathological processes of hormone-dependent diseases, such as breast, endometrial, and ovarian cancers, as well as osteoporosis. The biological actions of estrogens are mediated by binding to one of two specific estrogen receptors (ERs), ERα or ERβ. Both are ligand-regulated transcription factors.In order to gain desirable biological activities, as well as explore how ER works, a lot of ER ligands were synthesized. In this paper, our work are divided into three parts:1) To probe the importance of the heterocyclic core of estrogen receptor (ER) ligands, we prepared a series of thiophene-core ligands for ER by Suzuki cross-coupling of aryl boronic acids with bromo-thiophenes, and assessed their receptor binding and cell biological activities. The disposition of the phenol substituents on the thiophene core, at alternate or adjacent sites, and the nature of substituents on these phenols all contribute to binding affinity and subtype selectivity. Most of the bis(hydroxyphenyl)-thiophenes were ERβ selective, whereas the tris(hydroxyphenyl)-thiophenes were ERa selective; analogous furan-core compounds generally have lower affinity and less selectivity. Some diarylthiophenes show distinct superagonist activity in reporter gene assays, giving maximal activities2-3times that of estradiol, and modeling suggests that they have a different interaction with the hydrogen-bonding residue in helix-11. Ligand-core modification may be a new strategy for developing ER ligands whose selectivity is based on transcriptional activity greater than that of estradiol.2) Estrogen receptors are known drug targets that have been linked to several kinds of cancer. The structure of the estrogen receptor ligand binding domain is available and reveals a homodimeric layout. To seek good tools for the study of dimerization, we have designed and synthesized a series of bivalent ligands for estrogen receptors with differing in the nature and length of the spacer and choice of monomeric ligands. The best compound has an affinity of11.41for ERa and18.14for ER(3incorporated with a spacer length of20.5A. Bivalent ligands containing cyclofenil and ferrocenyl phenols displayed a moderate binding affinity and noteworthy functional activity compared to the original monomeric ligand. Further cell activity and X-Ray crystalgraphy is in progress. 3) The progression of many cancers and other proliferative disorders such as endometriosis is exacerbated by inflammation, and agents that block both the inflammatory and proliferative drives could prove to be very effective therapeutics. After screening numbers of ER ligands, we found that oxabicycloheptene sulfonate stabilize a unique conformation of the ER. This conformation enables OBHS has little effect on breast cancer cell proliferation, yet effectively blocks NF-κB signaling of inflammatory pathways. Thus,using structure-based design on OBHS, we synthesized a series of C-16and C-17modificaition estradiol analogs and introduced11β-methyl and ethyl group to enhance binding affinity. Further biological results is in progress. We hope to optimize the biocharacter of ER ligands to have potent anti-inflammatory activity without stimulating reproductive organs or breast cancers.Overall, based on structural-guided design, biological evaluation and molecular modeling, We explored the superagonist selective ER beta thiophene ligands, new ER bivalent ligands, and compounds that have both antitumor activity and anti-inflammatory at molecular level. The structure-activity relationships of synthetic ligands, biological activity and the mechanism of action of ligand are analyzed. According to the structure of lead compounds, further optimization is in progress. Our work has contributed to the discovery of new selective estrogen receptor modulators and provied important reference value and significant guidence for the following research.