Synthesis,Structural Modification And Biological Evaluation Of Ibrutinib

With the improvement of living standards,cancer is becoming more and more common in people’s lives,and it has become the second leading cause of death in the world after cardiovascular disease.Mantle cell lymphoma(MCL)is a rare B-cell non-Hodgkin’s lymphoma,which is invasive,characterized by high malignancy and poor prognosis,and can proliferate rapidly.The disease can improve the prognosis with traditional treatment methods,but it is still incurable,and MCL has a poor response to conventional treatment,so it is especially important to find a new MCL treatment.At present,with the in-depth study of the pathogenesis of MCL,small molecule targeted therapy has made some progress.However,The B cell receptor(BCR)signaling pathway is an important pathway to promote the growth and survival of lymphoma.The over-activation of BCR signaling pathway has a certain influence on the occurrence and development of B-cell tumors.And Bruton’s tyrosine kinase(BTK)is a key molecule in the BCR signaling pathway,which can regulate the cell processes such as survival,proliferation,activation,differentiation and maturation of B cells,so it is very important for treating MCL to target BTK.Ibrutinib(IBN)is the first commercially available BTK covalent inhibitor for the treatment of Mantle cell lymphoma(MCL),Chronic lymphocytic leukemia(CLL)and Wadenstrom macroglobulinemia(WM).However,with the application of IBN,MCL patients are resistant to it and die within 12 months.BTK C481S mutation is common in these patients that the catalytic domain 481 cysteine(Cys 481)of BTK is mutated to serine(Ser 481),so BTK loses the ability to covalently bind to the acrylyl side chain in the IBN structure,which results in decreased binding capacity of IBN to BTK protein.Therefore,the search for novel BTK inhibitors has certain significance for the treatment of MCL.We selected a suitable synthetic route to synthesis the positive drug Ibrutinib by reviewing the relevant literature.We then use Ibrutinib as a lead compound,and replaceing the parent-linked piperidine ring in IBN with a benzene ring and extending the link between the pyrazolopyrimidine ring and the terminal benzene ring,while introducing it on the terminal benzene ring.So we can get 24 target compound with different substituents.The structure of the target compound was confirmed by hydrogen spectrum(1H-NMR),carbon spectrum(13C-NMR)and mass spectrometry(MS).In BTK kinase inhibitory activity assay,some compounds inhibited BTK at a concentration of 10 μM,but at a concentration of 1 μM,Only LG6 and LG21 have an inhibition rate of more than 50%.However,compared with IBN,the activity is relatively poor.In the MCL cell growth inhibitory activity,Most of the compounds were found to have certain inhibitory effects on Mino and Jeko-1 cell lines of MCL.The IC50 values of the compounds LG1,LG5-LG11,LG21 and LG23-LG24 were about 10 μM for both cell lines.Although the inhibitory activity of this series of compounds against Jeko-1 was weaker than that of the positive drugs,compounds LG1-LG2,LG4-LG11,LG16,LG18,LG21 and LG23-LG24 on Mino cells were superior to the positive drug IBN.In addition,we selected LG1,LG5-LG11,LG21,LG23-LG24 to determine the growth inhibitory activity of IBN-resistant cell lines Z138,Maver-1 and BTK knockout cell line Jeko-1 KO#11.The results showed that the most potent inhibitor of MCL cells in this series was LG21,and the IC50 for the five cells of Mino,Jeko-1,Z138,Maver-1,and Jeko-1 KO#11 were respectively 5.4μM,4.3μM,2.5 μM,6.1 μM,5.3 μM.Finally,we tested the inhibitory activity of LG21 for 37 kinases at a concentration of 1 μM.The data indicates that the compound LG21 has almost no inhibitory activity against these 37 kinases.Although this series of compounds did not achieve the effect as our expected,but they has a certain inhibitory effect on MCL cells,so the mechanism of these compounds will be further studied.