Design,Synthesis And Biological Evaluation Of SERMs Containing Phenylselenyl Group

Breast cancer is one of the most common cancers in women all over the world.It is named as breast cancer because it originates from the breast tissue.The risk of breast cancer increases with age.Breast cancer is the second leading cause of cancer death among women in the United States,although developed countries report a survival rate of almost 90 percent within five years.Scientific research is developing continuously,but the treatment drugs and treatment methods for breast cancer are not ideal for improving patients’conditions and quality of life.Estrogen plays an important role in the regulation of human physiological functions,but its overexpression is one of the main factors leading to breast cancer.Estrogen receptor（ER）is a ligand-dependent transcription factor with two subtypes of ER and ER.Estrogen mainly plays a role in regulating gene expression through ER mediated signaling pathways,so Estrogen receptor is a major target for the development of drugs related to breast cancer.Selenium,an essential trace element in human body,has a wide range of physiological effects and plays an important role in anti-inflammation,anti-cancer and neuroprotection.Studies have shown that selenium also plays an important role in anti-tumor.Selenium-containing compounds have been proved to promote apoptosis of cells to a certain extent,but also cause mitochondrial dysfunction,inhibit microtubule protein aggregation,block cell cycle and other ways,so that it has a very good inhibitory effect on tumor cells and tissues.Selective estrogen receptor modulators（SERMs）is currently one of the most main drugs for breast cancer,namely in different organizations have different excited or antagonism effect,with the wide use of these drugs such as tamoxifen,also increase the risk of drug resistance and many side effects,therefore,research new SERMs especially for cells play a role of resistance to drugs is very necessary.The synthetic category based on the early stage of the team,we have double oxygen bridge heptene OBHS class structure,because of the special three-dimensional structure of the molecule and its containing phenol groups can occur with estrogen receptor in the pockets of amino acid residues hydrogen bonding well into the estrogen receptor pocket produce estrogen antagonist role,based on the molecular structure transformation have also made very good progress,as in the SAHA,introduced the structure,and the derivatives of ferrocene group etc can be very good improve its biological activity,at the same time considering the selenium compounds in the important function of cancer prevention and control,Through the analysis of many selenium-containing compounds,we found that the benzene-selenium group may be an excellent anti-tumor active group.Therefore,based on the previous work of our research group,we designed to introduce the Phenylselenyl group into the molecular structure of oxybris-bicyclopentene SERMs（OBHS）to synthesize a series of OBHS derivatives containing Phenylselenyl group.In our design,OBHS compounds containing Phenylselenyl group can achieve better anti-tumor activity and higher safety at the same time.Therefore,we synthesized important furan ring intermediates with different substituents in a high yield after a 8-step reaction,and then obtained the final product by Diels-Alder reaction with the corresponding sulfonates with different substituents.We also preliminarily studied the anti-breast cancer activity of these compounds through biological cell experiments.According to the bioactivity test results,the conjugates of these Ph Se-OBHS showed good ER affinity and most of them were ERαselectivity,among which II-13m and II-13n had the highest relative binding force,and their RBA values were 6.62%and 6.39%,respectively.In vitro Cells inhibition experiment,except compound II-22a,breast cancer activity of other compounds are stronger than4OHT,when the base phases are same,the substituent in para compounds showed stronger resistance to breast cancer activity,The IC₅₀ value of the best compounds II-13i reached 2.08μM,we preliminary studied by molecular docking experiment with ERα,proved that the introduction of Phenylselenyl group can form hydrogen bonding interaction with estrogen receptor cavity pocket,which can be a very good combination with estrogen receptor improve the antitumor activity of compound.Based on good activity of this series of compounds,and amide chain are good for the biological activity as a short chain at the same time,with compounds containing amide short chain upgrading also made very good progress,we design contain amide short chain groups of benzene selenium is introduced into the OBHS designed and synthesized 6 OBHS derivatives containing amide short chain,this series of containing amide short chains of Phenylselenyl on sulfonic acid ester compounds showed activity of ERαgood affinity,the compound III-22b RBA value can reach6.76%,its corresponding IC₅₀ value concentration reached 3.43μM.This study provides a basis for the application of selenium compounds in anti-tumor compounds.