Design,Synthesis And Mechanism Reseach Of O-Diaryl-Five-Member-N-Heterocycle Small Molecule With Anti-Cancer Activities

Pancreatic cancer is one of the most common and lethal cancers in the worldwide,of which diagnosis is difficult to made.About 52%pancreatic cancer patients have cancer metastasis at diagnose,leading to a high mortality rate,with 3%for 5 years surviaval rate.Clinically,there is a great need for novel therapeutic drugs to treat pancreatic cancer,especially the metastasized pancreatic cancer.myoferlin(MYOF),a member of Ferlin family,plays an important role in the proliferation and metastasis of cancer cells,by regulating vesicle trafficking to affect the expression,secretion and distribution of cancer-related proteins and the metabolism of lipid as well as the energy utilization,etc..In clinics,the overexpression of MYOF was statistically positively related with tumor metastasis and low survival rates.In recent years,MYOF is found to be highly expressed in pancreatic cancers by clinical statistic method,while be in a low expression in non-tumor tissue.Therefore,MYOF can be a potential target for pancreatic cancer treatment.The development of MYOF inhibitor is of great significance.Recently,our team have reported the first MYOF inhibitor coded as WJ460,but the subsequent reseach found that it need be further improved for the binding affinity with MYOF and metabolism stability.Therefore,in this thesis,we applied chemical structure modification strategies such as replacing the key scalffold to optimize the structure of WJ460 systematically.First,we replaced the key scalffod of the WJ460,thiazolidinone,with five-member N heteroaromatics,leading to the discovery of 1,2,3-triazole or 1,2,4-triazole containing analogues that showed moderate anti-proliferation and anti-metastasis activities.Subsequently,we applied substituent optimization on the triazoles and found ethyl group was preferred on both triazoles and 1,24-triazole was superior to 1,2,3-triazole in the anti-cancer activities.Then the diphenyl groups and their substituent were optimized.The replacement of ring A with pyrimidine lead to a series of compounds with good activities against pancreatic cancer cells.Among them,compound 4u exerted effective anti-proliferation and anti-migration activities in a low concerntration against the proliferation and metastasis of PANC1 cancer cell line(IC₅₀:0.13±0.04?M and 0.11±0.03?M,respectively).Results of surface plasmon resonance(SPR)compound 4u(K_D=0.09?M)showed14-fold increase in affinity with MYOF-C2D than that of compound WJ460(K_D=1.33?M).The solubility of compound 4u showed more than 100-fold increase than that of compound WJ460.Quantification of bioluminescence on the BALB/C nude mice lung metastasis model showed compound 4u significantly inhibited the the metastasis of cancer cell,superior to gemcitabine that is the first-line therapy drug of pancreatic cancer,and had no siginifcant toxic side effect and adverse reaction.Moreover,compound 4u showed significant improvement in metabolic stability without inhibition on six main CYP isozymes.Briefly,in this thesis we reported a series of 1,5-diaryl-1,2,4-triazoles small molecule compounds containing pyrimidine,which effectively suppressed the proliferation and metastasis of pancreatic cancer cell lines,via targeting MYOF,a cancer-related protein that regulates the vesicle trafficking.The results of SPR showed the compound 4u have a 14-fold increase in the binding affinity than that of hit compound WJ460.The animal model in vivo showed compond 4u showed superior effect to gemicitabine,the pancreactic cancer first-line treatment drug.The solubility and metabolism stability of compound 4u also improved siginificantly compared to the hit compound.The series of lead compouds that tareget MYOF provide a new strategy for targeted therapy of pancreatic cancer.