Design,Synthesis And Bio-evaluation Of SERMs Based On Selenophene-core Structure

Therapeutic targeting of the estrogen receptor(ER)has traditionally involved direct disruption of the surface coactivator binding sites by a basic side chain(BSC)that is a characteristic structural feature of selective estrogen receptor modulators(SERMs),such as tamoxifen and raloxifene.But the long-term use of SERMs drug would cause serious side-effect and secondary drug resistance.So,it’s important to find some novel ligands with slight side effect for breast cancer therapy.Recent investigations reveal that breast cancer metastasis is one of the major killers for the females’ deaths,which is not only related to the cancer cell itself but also the uncontrollable inflammatory.The control of both the inflammatory and proliferative drives could be the key to therapeutics.In order to gain "ideal" SERMs,in this paper,our work are divided into two parts:1)To prepare more potent,fully antagonistic analogs in the selenophene series for breast cancer therapy,in this work,basic side chains were introduced into the selenophene scaffold to form series of new selenophene derivatives and their biological activity as subtype-selective antagonist for the estrogen receptor was further explored.Interestingly,most of the compounds in series I that possessed the basic side chain in the 2-phenol moiety exhibited better binding affinity for ERa.On the contrary,the vast majority of series II that located the basic side chain in the 3-phenol moiety displayed moderate levels of ERβ selectivity.The most promising compound of this study is 16c,and the triphenyl substituent ligand showed good transcriptional activity for ERa(IC50 = 13 nM)which made 16c the most potent antagonist for ERa of the whole series and is 66-fold better than the best compound in selenophenes without a BSC.It was notable that these compounds 9a,12b,12h,and 16a-c showed antiproliferative effects better than that of 4-hydroxytamoxifen in breast cancer MCF-7 cells.The moldeling study showed that the introduction of basic side chain has a significantly effect on antiproliferative activity of these compounds via directly interacting with helix 12.These new ligands could act as models for the development of novel agents to improving therapeutics that target the estrogen receptor.2)In order to investigate the importance of selenophene or thiolphene core acyl hydrazone as dual-functional ligands,we designed and prepared some compounds based on selenophene or thiolphene-core ligands,and investigated the anti-proliferative activity and anti-inflammatory activity.We plan to investigate the RBA value and transcriptional activity of these ligands to further evalute biological activities of these dual-functional SERMs.Our work carve a path for the development of new SERMs and provide an important blueprint for the coming research.