Trifluoromethylselenylation And Cytotoxicity Assays Of Amino Acids And Peptides

In the past decades,chemists have been working on the structural modification of amino acids and their derivatives,in which the introduction of fluorine atoms or fluorine-containing groups into such compounds has proved to be an effective way to improve their biological activities.From the initial fluorination of these compounds to the successful synthesis of trifluoromethoxy-,trifluoromethylthio-and trifluoromethylselenyl-substituted amino acids,chemists have been continuingly studying the fluorine-modification of these active molecules.Combining the trifluoromethoxy-and trifluoromethylthio-modification of amino acids with their biological activities,we endavored to synthesize trifluoromethylselenyl-containing amino acids and peptides by using[Me₄N][Se CF₃]as a cheap,safe,stable,and easy to obtain trifluoromethylselenylation reagent.Then,we performed the biological evaluation of these compounds,aiming for discovering novel biologically active molecules.This thesis mainly focuses on the following two parts:In the first part,we developed two simple and convenient routes to successfully prepare trifluoromethylselenylated amino acids and peptides,including methyl（R）-2-amino-3-（（trifluoromethyl）selanyl）propanoate hydrochloride（6a）,methyl（S）-2-amino-4-（（trifluoromethyl）selanyl）butanoate hydrochloride（6b）,methyl（2R,3R）-2-amino-3-（（trifluoromethyl）selanyl）butanoate hydrochloride（6c）,methyl（R）-2-（（S）-2-amino-3-phenylpropanamido）-3-（（trifluoromethyl）selanyl）propanoate hydrochloride（12a）andmethyl（R）-2-（2-aminoacetamido）-3-（（trifluoromethyl）selanyl）propanoatehydrochloride（12b）.At the beginning,we used hydroxyl-containing amino acids as the raw materials to produce their p-toluenesulfonate or bromide intermediates,respectively,through sequential amino protection,carboxyl protection,and esterification or substitution.Then,the intermediates were treated with[Me₄N][Se CF₃]under a nitrogen atmosphere,followed by deprotection,to give the corresponding target molecules in 8-49%total yields.In the second part,the in vitro cytotoxicity assays of the prepared trifluoromethylselenyl-amino acids and-peptides including the target molecules and the corresponding intermediates were conducted.The results revealed that（R）-2-amino-3-（（trifluoromethyl）selanyl）propanoate hydrochloride（6a）,methyl（R）-2-（（S）-2-（（tert-butoxycarbonyl）amino）-3-phenylpropanamido）-3-（（trifluoromethyl）sel anyl）propanoate（8a）andmethyl（R）-2-（2-aminoacetamido）-3-（（trifluoromethyl）selanyl）propanoate hydrochloride（12a）were more effective cell growth inhibitors than the other tested CF₃Se-substituted derivatives towards human breast cancer cell lines MCF-7,human colon cancer lines HCT-116,and human ovarian cancer lines SK-OV-3 cells,with their IC₅₀ values being less than 10 u M for MCF-7 and HCT-116 cells.In conclusion,we have successfully prepared trifluoromethylselenylated amino acids and peptides through reliable synthetic routes,which have shown advantages such as short steps,safe and easy to obtain reagents,simple operation,and mild conditions.These findings break the current limitation on trifluoromethylselenyl amino acids.Moreover,the results of in vitro cytotoxicity assays provide more insights into the biological activity of this type of compounds.This work would be a guide for application of trifluoromethylselenyl group in the design and development of new drugs.