Optimization Of Synthetic Route Of α,β-unsaturated Ketone Oxadiazole Compounds And Its Derivatives Synthesis And Antitumor Activity Evaluation

Malignant tumors have posed a serious threat to human health and survival.At present,there are about 600 million deaths worldwide due to malignant tumors,and the number of deaths has increased year by year.Target molecular therapy drugs are characterized by small side effects,good efficacy,the development of targeted therapeutic effect of anti-tumor drugs is related to the field of research hot spotsThere are seven subtypes in the mammalian glutathione transferase family,in which glutathione S-transferases π,GST7π are the highest expression levels.Highly expressed GSTπ was found in human tumor cells and pre-cancerous tissues of ovarian cancer,non-small cell lung cancer,breast cancer,liver cancer,colon cancer and lymphoma.On the one hand,the highly expressed GSTπ can act as a phase Ⅱmetabolic enzyme to accelerate the efflux of antitumor drugs in tumor cells,thereby inducing the production of tumor cell resistance;On the other hand,high expression of GSTπ can inhibit the activation of tumor cells by interacting with the relevant factors and important kinase interactions in the apoptotic pathway.Thus,GST71 can be used as a target for antitumor drug research.Ethacrynic acid(EA)has been used clinically as a diuretic and is the first drug to be used as a GSTs inhibitor.EA on the one hand can be combined with the substrate binding site of GSTs.the activity of a,μ,π subtype directly inhibited;on the other hand by Michael addition directly with the GSH binding to inhibit GSTs,the mechanism is EA of α,B-unsaturated ketone fraction and the GSH structure of the mercapto nucleophilic addition reaction,which depleted GSH.In addition,EA can be combined with chemotherapy drugs to inhibit drug efflux to increase the concentration of drug in tumor cells,combined play an anti-tumor effect,high concentrations of EA can also directly inhibit tumor cell growth and induce apoptosis.However,EA’s diuretic effect and lack of GST isoenzyme specificity limit its clinical application,so the structure of its derivatives to optimize the derivatives also appear one after another.With EA as the lead compound and glutathione transferase as the target,we have combined the synthesis of carboxylic acids,esters,oxazoles and 1,2,4-oxadiazole-containing EA derivatives.The compounds 6r,6s,6u were screened,Has good in vitro and in vivo anti-tumor activity.We also studied the mechanism of action of the three,which can induce apoptosis of SW620 cells,and interfere with the cell proliferation cycle,so that it blocked in the S phase,thus play a role in inhibiting tumor cell proliferation;6s and 6u-induced apoptosis of HL-60 cells were mediated by Myeloid cell leukemia-1(Mcl-1)and X-linked inhibitor of apoptosis protein(XIAP)Aspartate cysteinyl aspartate specific proteinase-9(caspase-9)mediated endogenous apoptotic pathway,also can inhibit the extracellular regulatory protein kinase(ERK)signaling pathway and thus affect the translation of protein.We conducted a preliminary pharmacokinetic study,with good drug resistance,it is necessary to determine a high yield of 6r,6s,6u environmental preparation route.We have been optimized on the basis of the existing route to overcome the inconvenience of the original route operation,low yield,the use of poor solvents and other defects,to determine a high yield of 6r,6s,6u environmental preparation method,the method uses 2,3-dichlorophenol as raw material,through the protection of phenolic hydroxyl groups,Fu Ke acylation,phenolic hydroxyl protecting group,nucleophilic substitution,ester hydrolysis,aldol condensation,dehydration,ring into 6r,6s,6u.The whole reaction route does not use a class of reagents,the reaction conditions are mild,stable and controllable,the post-processing is simple,the whole route does not need column chromatography to purify the intermediate or final product,easy to carry out industrial production,yield and purity are high,6r,6s and 6u were about 45.2%,50.8%and 56.7%respectively.The HPLC purity was 99.1%,99.2%and 99.3%,respectively.Based on the work done by the research group,we used 6s,6u as the lead compound,and retained the substituted benzene ring structure at the 3-position of the male ring 1,2,4-oxadiazole ring and the oxadiazole ring,and removed the methylene group in the α,β-unsaturated ketone structure Structure,in the carbonyl beta position with different substituents of the phenol,the design of W series of 20 compounds;theα,β-unsaturated ketone structure fragment in the 6s and 6u structures is retained,and the substituted benzene ring at the 3-position of the 1,2,4-oxadiazole ring and the oxadiazole ring is substituted with an amide bond through a piperazine ring,Different pyrimidine splicing rings are linked to the structure of both the EA and the different intermediates in the piperazine ring by forming the amide bond to obtain the Y series of 4 amide compounds.The structures of the synthesized compounds were not reported in the literature.We determined the compounds W1-W11 and compounds 6s,6u and the listed mantle cell lymphoma(MCL)treatment of erlotinib(IBN)on MCL cell lines Mino.Rec-1,Jeko-1,Maver-1,The inhibitory activity of Z138 was different from that of other MCL cell lines except for compounds W4,W6 and W11.However,compared with IBN,6s and 6u were poor;Compound W10 is a better activity,IC50 of Mino,Rec-1,Jeko-1,Maver-1,Z138 is 53,42.81,26.39,15.23,14.03μM,but relative to IBN,6s,6u difference.In general,this series of compounds is not ideal for the activity of MCL cell lines.From the structural point of view,IBN,6s and 6u all have α,β-unsaturated ketone fragments,which may be the key fragment of compounds that inhibit the activity of MCL cells.We also measured the growth inhibitory activity of compounds W1-W20 and EA.6s,6u on PC-3 in prostate cancer cells.The IC50 of 6s and 6u to PC-3 were 2.82μM,3.09μM,the IC50 of compounds W6 W7,W8,W9,W11,W12,W19,W20 is 31.84,28.94,17.45,16.40,20.31,26.36,22.59,21.94μM,respectively,compared with 6s.6u there is a certain difference.Y series of compounds showed good inhibitory activity against PC-3.The IC50 of Y1-Y4 to PC-3 was 0.26,0.28,0.53 and 0.25μM,respectively,better than the lead 6s(2.82μM),6u(3.09μM).We can show that α,β-unsaturated ketones are structural fragments that play a key role in the growth inhibitory activity of tumor cells and it is a good optimization strategy to retain the a,P-unsaturated ketone structure to replace the heterocycle.Further,we can also study the mechanism of the Y series compounds.