Designment Synthesis,Characterization And Antitumor Activity Studies Of Novel Pyrazole Derivatives

In this dissertation,we designed and synthesized more than 100 new pyrazole derivatives with different excellent antitumor active groups,such as 1,4-pentadien-3-one,substituted pyridine,thiazole,oxadiazole and thiadiazole,through organic splicing technique.All the resultant compounds were analyzed by elemental analysis,1H NMR and 13C NMR.In order to obtain effective target product and construct the relationship between molecular structure and antitumor activity,we also used MTT method to investigate their antitumor activity in vitro.All the above studies can provide a principle for the rational designment of antitumor drugs based on pyrazole.The main results are as follows:1.Designment,Synthesis,characterization and antitumor activity studies of pyridine-1,4-pentadien-3-one-pyrazole derivatives(A).We found that all the three rings,including pyridine,1,4-pentadien-3-one and pyrazole have good antitumor activity.In order to obtain the activity superposition or synergistic effect of these antitumor active agents,the above three pharmacophores spliced together by a chemical method and different substituents are introduced.In this study,MTT assay was utilized to detect the inhibitory activity of compounds in human pancreatic cancer cells(Panc-1),human hepatocellular carcinoma cells(HepG2)and human gastric cancer cells(SGC-7901).We prepared and characterized nine target compounds(AVIIa~AVIIi)through five steps from the obtained intermediates.Anti-tumor activity studies have found that most compounds have a good inhibitory activity against HepG2 in three cancer cells,IC50 of the target compound is much higher than the sorafenib positive control group,and even up to 100 times of the control group.It is also apparent that when R2 is 2-chloropyridine-5-methylene(R1 = H),the substituents at the 3-position of the benzene ring are halogen(AVIId and AVIIf)relative to the data from the structure-antitumor activity)Or a 2,4-position substituent is a chlorine atom(AVIIi),it helps to increase the antiproliferative activity against HepG2.2.Designment,Synthesis,characterization and antitumor activity investigation of thiazole-1,4-pentadien-3-one-pyrazole derivatives(B).Thiazole,1,4-pentadien-3-one and pyrazole rings all have good antitumor activity.In order to obtain the activity superposition or synergistic effect of these antitumor active agents,the above three pharmacophores are spliced together by a chemical method and different substituents are introduced.In this part,MTT assay was used to detect the inhibitory activity of compounds in human pancreatic cancer cells(Panc-1),human hepatocellular carcinoma cells(HepG2)and human gastric cancer cells(SGC-7901).We synthesized and characterizednine target compounds(BVIIa?BVIIq)from the intermediates through five steps.Anti-tumor activity studies have found that most compounds have a good inhibitory activity against HepG2 in three cancer cells,IC50 of the target compound is much higher than the sorafenib positive control group,and even up to 10 times of the control group.We investigated the structure-antitumor activity data found that when R2 is 2-chlorothiazole-5-methylene,R1=OMe,R3 is 3-methyl substituted compound BVIIb,R3 is 2-chloro substituted compound BVIIg Than other derivatives showed better anti-HepG2 activity.R2 is 2-chlorothiazole-5-methylene,R3 is 2-chloro or 2-bromo,and R1 is OMe-substituted compound BVIIg or BVIIi exhibits better antitumor activity than the corresponding R1-substituted compound BVIIp or BVIIq.3.Designment,Synthesis,characterization and antitumor activity analysis of pyrazoleoxime-pyridine derivatives(C).We have designed and prepared a series of compounds that have not been reported as potent compounds.In this part,MTT assay was used to detect the inhibitory activity of compounds in human pancreatic cancer cells(Panc-1),human hepatocellular carcinoma cells(HepG2)and human gastric cancer cells(SGC-7901).We synthesized and characterizednine target compounds(CIXa?CIXw)from the intermediatesthoughfive steps.The inhibitory activity of target compounds on human pancreatic cancer cells(Panc-1),human hepatocellular carcinoma cells(HepG2)and human gastric cancer cells(SGC-7901)was screened and evaluated,sorafenib and 5-fluorouracil were positive controls.The results showed that some of the three cancer cells,the target compound on HepG2 antiproliferative activity is more effective.In these compounds,IC50 values for HepG2 were 1.53-17.27 ? M for compounds CIXb,CIXg,CIXI,CIXp,CIXq,CIXr,CIXs,CIXt,CIXu,and CIXv.The IC50 values of these compounds were significantly higher than those in the 5-fluorouracil control group(IC50=35.67? M),meaning that the target compound had better anticancer activity.Especially compound CIXr,which inhibits HepG2 up to 23 times of that of the control.Based on the data on the structure-antitumor activity,we found that when the mercapto group is at the 4-position,R1 is methyl,the 3-fluoro substituted compound CIXp and the 4-chloro substituted compound CIXr show a more potent inhibitory activity against HepG2.4.Designment,Synthesis,characterization and antitumor activity analysis of pyrazoleoxime-oxadiazole derivatives(D).Oxadiazole as an extremely important component of azole derivatives,which has good antitumor activity,we introduce oxadiazolebenzenesulfonyl group as an active group into the pyrazole matrix,The lead compound is modified with the benzene ring attached to the oxygen to desirably wait until the target compound has good antitumor activity.The prepared intermediates were synthesized by the reaction of 20 compounds,and all related compounds were synthesized.The inhibitory activity of target compound DIXa?DIXr on human hepatocellular carcinoma cells(HepG2),human gastric cancer cells(SGC-7901),HCT-116 colon cancer cells was screened and evaluated.In addition to compounds DIXI on the three kinds of cancer cells did not show any inhibitory activity,the rest of the compounds are have a good inhibitory activity only for HepG2,the highest IC50 value is only 0.03? M(DIXe).5.Designment,Synthesis,characterization and antitumor activity analysis of pyrazoleoxime-thiadiazolederivatives(E).We synthesized 17 new target compounds from the prepared intermediates by five steps(EIXa?EIXq)).The inhibitory activity of target compounds 9a~9q on human hepatocellular carcinoma cell line HepG2,human gastric cancer cell line SGC-7901,HCT-116 colon cancer cells was screened and evaluated.Compounds EIXa?EIXi showed good inhibitory activity against HepG2 with IC50 of 0.59~6.44 u M,and the rest of the compounds did not show any inhibitory activity on the three kinds of cancer cells.6.Designment,Synthesis,characterization and antitumor activity analysis of di(tri)fluoropyrazole-oxadiazole derivatives(F).A total of 26 target compounds were synthesized by a five-step reaction:difluoropyrazole-oxadiazole derivatives FVIa?FVIo;trifluoropyrazole-oxadiazole derivatives FVIIa?FVIIk.The inhibitory activity of target compounds on human hepatoma cells(HepG2),human gastric cancer cells(SGC-7901),HCT-116 colon cancer cells were screened and evaluated.Only compounds FVIc,FVIe and FVIIe showed better inhibitory activity against HepG2,and the other compounds did not show inhibitory activity on the three kinds of cancer cells.