| Cancer treatment is now a global concern.Although tumor can be removed quickly by surgery,it is rare to achieve complete resection.Surgically escaped tumor cells can be further controlled by means of adjuvant therapy,radiotherapy and chemotherapy,however,there is currently no cure for the proliferation of tumor cells.Cancer can usually recur.Cathepsins are a class of proteases found in all animals and other organisms,which breaks down proteins by hydrolyzing chemical bonds.The family has about a dozen members whose structures,catalytic mechanisms and the substrates vary.Cathepsin B is a cysteine protease,which is widely found in many tissues of various mammals,and is one of the best-studied protease.Cathepsin B is involved in cell apoptosis,autophagy and cancer development,and therefore is a potential target for cancer protection.Researches suggest that cathepsin B is closely related to a variety of cancers,including breast cancer,gastric cancer,lung cancer,and bladder cancer.Tumor tissues are detected with a significant rise of cathepsin B,which shows that cathepsin B has a important role in tumor proliferation and can be used as an potential biomarker of cancer.Cathepsin B helps tumor cells to metastasize and angiogenesis by hydrolysis of proteins.Therefore,cathepsin B inhibitors are considered to be a kind of promising potential drugs for developing anti-tumor drugs and will provide new insights into cancer treatment.Although a number of inhibitors of cathepsin B have been identified currently,they have encountered bottlenecks due to poor selectivity and/or poor stability.The aim of this study is to find a better selective inhibitor of cathepsin B.Given the fact that the activity domain of cathepsin is highly conserved,novel cathepsin inhibitors can be designed based on the active sites and substrate binding domains that are necessary for the enzymatic reaction.Cathepsins are composed of eleven members,belonging to the family of papain.The structure of cathepsin B is very similar to cathepsin K,L and S.Its active sites are divided into several sub-sites,and the cathepsin B inhibitors need to be bound to S1' and S2'sub-sites simultaneously,thus,the development of highly specific inhibitors of cathepsin B is particularly important.Recent studies have shown that derivatives of epoxysilyl peptides can inhibit cathepsin B by covalently linking their thiol groups of ethylene oxide to the Cys29 residue of cathepsin B.E64 d is a highly selective and potent inhibitor of cathepsin B,which binds to the S1'-S2' sub-sites and is a derivative of epoxy succinic peptide.In order to lower experimental cost,increase success rate and also reduce other risks,the current study employs Me-too approach as the design strategy.Through systematic review and evaluation of previous synthesized cathepsin B inhibitor,the epoxy succinic acid was selected as the core structure of the novel cathepsin B inhibitors.By analyzing the structure-activity relationship of synthesized derivatives of epoxy succinic acid,E64 d was chosen as the reference compound.The sulfur series inhibitors were synthesized for the first time.Moreover,to evaluate the steric hindrance effect,forty-eight new compounds were synthesized including twenty-three methylthio-substituted compounds,twenty-four benzyl-sulfide containing compounds,one trityl-substituted compounds as well as the reference compound E64 d.In the current study,by adding different substituent groups to either B or C part of E64 d,cathepsin B inhibitors of epoxy succinic acid derivatives with higher selectivity and potency were synthesized.These novel compounds must be able to keep the inhibitory activity of cathepsin B and also reduce the inhibitory activity of other cathepsins(cathepsin K,cathepsin L).In order to improve the inhibitory activity,Watanabe et al.introduced oxygen atom to part B of the epoxy succinic acid derivatives.Sadaghiani's team synthesized a series of epoxy succinic acid inhibitors containing benzene rings in part B.However,these compounds displayed reduced inhibitory and/or selectivity.The current study successfully designed and synthesized a series of epoxy succinic acid derivatives having methionine substituent(sulfur atoms)in part B.Compared with leucine,methionine substituent shares some common properties,such as the space steric hindrance and thelength of carbon chain.Therefore,new methionine substituting compounds may only have a minimal influence on the cathepsin B inhibition activity.We also synthesized a series of epoxy succinic acid derivatives with cysteine type substitution.Compared with those previous substitutions,there were much obvious change of steric hindrance when introducing cysteine substituent.The current study aims to explore the effect of steric hindrance on cathepsin B inhibitory and selectivity improvement by introducing different substitution to part B.In addition,in order to better understand the structure-activity relationship of inhibitory and selectivity,twenty-three cathepsin B inhibitors with different part C substituents were synthesized,and a comprehensive comparative study was conducted among these novel compounds.Results show that introducing sulfur-containing alkyl and benzene ring to replace the 2-methyl propane moiety of E64 d significantly improved the potency.In summary,a series of compounds were synthesized by introducing substituents with different lengths and hydrophobicity of the carbon chain to either B or C part of the epoxy succinic acid.In the B part,compared with benzene ring sulfur substituent,alkyl sulfur substituent-containing compounds have better selectivity and inhibition toward cathepsin B.Moreover,current study shows that when the C part is substituted with n-hexyl with six carbons,the resulting compounds are more potent than the compound E64 d.Additionally,when benzene ring is added into the substituents,the selectivity and inhibition are further improved.In the further work,the effects of different carbon chain substitutions in part C and the introduction of benzene ring on the activity will be investigated. |
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