Design,Synthesis And Evaluation Of Antitumor Bioactivity Of 1-(4-substituted Benzyl)-2,3-dione Oxime Derivatives

Tumor is a disease that seriously harms human health.In the past 20 years,with the increase in the incidence and mortality of cancer,it has become one of the most concerned diseases in the field of medical research.According to data from the World Health Organization’s Cancer Research Institute,there were more than 14 million new cases of global malignancy in 2012,and approximately 8 million people died from malignant tumors,which is the main cause of death worldwide.Malignant tumors have become a major public health problem in China.Since 2010,malignant tumors have surpassed cardiovascular and cerebrovascular diseases and have become the number one cause of death among Chinese people.Mantle Cell Lymphoma(MCL)is a B-cell non-Hodgkin’s Lymphoma(NHL),a lymphoproliferative disorder.It is a rather rare disorder,comprising about 6-10%of all B cell lymphoma cases.The median age at diagnosis is 68 years and the disease is more prevalent in males than females.In 2013,ibrutinib was approved by the USFDA for the treatment of relapsed CLL and mantle cell lymphoma(MCL).In addition,ibrutinib also showed efficacy in diffuse large B-cell lymphoma(DLBCL).Although ibrutinib has a significant effect in a variety of B-cell malignancies,there have also been cases of primary drug resistance to Ibrutinib and acquired drug resistance.Patients who are resistant to Ibrutinib will be within 12 months of death.Therefore,research and development of new mantle cell lymphoma therapeutic drugs(especially for ibrutinib resistant mantle cell lymphoma)is of great significance.Isatin,also known as 2,3-dione indole,is an important class of indole derivatives.It is a comprehensive,multifunctional molecule that is a precursor to a large number of pharmacologically active compounds.Isatin is an endogenous compound commonly found in blood,the central nervous system,body fluids,and other human tissues.Isatin derivatives are endogenous natural compounds that have developed rapidly in the field of medicinal chemistry and exhibit a wide range of biological activities including antibacterial,antifungal,anticonvulsant,antiviral and antitumor activities.A series of isatin derivatives have been synthesized in the early stage of the laboratory.The compound Tii-6p has strong growth inhibitory activity on multiple mantle cell lymphoma(MCL)cells and prostate cancer cell(PC-3).4-amino-1,2-naphthoquinone compounds and MI-2 are MALT1 inhibitors,which have good inhibitory activity on MALT1.MI-2 is an irreversible covalent inhibitor of malt1 that can continuously inhibit the activity of MALT1 with an IC50 of 5.84 μM.And MI-2 contained the chloromethylamide moiety that can covalently bind to the active site of MALT1.MI-2 targets MALT1 activity in activated B-cell-diffuse large B-cell lymphoma(ABC-DLBCL)and chronic lymphocytic leukemia(CLL).The proteolytic activity of Malt1 is essential for survival of activated B cell subsets in diffuse large B-cell lymphoma(ABC-DLBCL).Therefore,Maltl inhibition is a promising therapeutic strategy for the treatment of this most common non-Hodgkin lymphoma subtype.In compound design,the heterozygous pharmacophore is an effective and commonly used method for synthesizing new drugs.Hybrids of two or more biologically active fragments have complementary pharmacodynamic functions or different mechanisms of action.It is expected that its synergistic effect can effectively treat cancer.We heterozygous the structure of Tii-6p and MI-2.The original 3,4-dichlorobenzyl is replaced by 4-chlorobenzamide benzyl of MI-2 at the 1 position on the basis of unchanged Tii-6p pharmacodynamic group 2,3-dione indole mother nucleus and 5-position amide.A series of new isatin derivatives were designed and synthesized.The structures of the target compounds were confirmed by 1H-NMR,13C-NMR and MS.The compounds had strong antiproliferative activity against multiple mantle cell lymphoma(MCL)cells(JVM-2,Z138,Rec-1,Jeko-1,Maver-1,Mino and Jeko-R)with IC50 values at the low micromolar level,which were better than the marketed drug Ibrutinib.Most of the compounds had better growth inhibitory activity against prostate cell line(PC-3)and human acute promyelocytic leukemia cell line(HL-60),which were better than the positive control drug MI-2.Overall,this series of compounds has good growth inhibitory activity against multiple tumor cells.Next we can study the mechanism of this series of compounds.