| With the development of molecular biology,the physiological processes in tumor cells,such as the tumor cell signaling transduction pathways,are elucidated and well understood,and it becomes known that the disturbance of these signal pathways is an important reason for the unlimited proliferation and metastasis of tumor cells.Because the abnormal kinase function in cell signaling pathway plays an important role in the occurrence and development of tumor,these key signal kinases become important targets for anticancer drug developments.In comparison with the traditional chemotherapy,molecular targeted drugs are more effective,higher selectivity and less side effects.As an intracellular phosphatidylinositol kinase,PI3K is an important intracellular signal transduction molecule.PI3K kinases are mainly divided into three categories,among which class I PI3K is most closely related to the development of tumors.According to the difference between catalytic subunit and regulatory subunit,class I PI3K is further divided into four subtypes,PI3Ka,PI3K?,PI3K8 and PI3Ky.PI3Ka and PI3K? are widely distributed in various tissues and organs.PI3K? and PI3Kry are mainly expressed in immune cells and hematopoietic cells.Therefore,selective PI3K8 or PI3Ky inhibitors and PI3K5/y dual inhibitors are of great significance for the treatment of hematological malignancies and immune cell-mediated diseases.The selective PI3K8 inhibitor idelalisib(CAL101)is approved by FDA for relapsed follicular B-cell non-Hodgkin's lymphoma and for relapsed chronic lymphocytic leukemia.In the previous research,based on crystal structural of PI3K? and the the binding mode of CAL-101,applying the conformational restriction drug design strategy,our group have designed and synthesized a series of novel quinazolinone selective PI3K?inhibitors and discovered two compounds with better isoform selectivity than the marketed drug CAL-101.In order to find novel selective PI3K? inhibitors,in this study,we used the more stable sulfonyl group to instead the quinazolinone carbonyl group,designed a series of 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives.The 2-nitrobenzenesulfonyl chloride,5-fluoro-2-nitrobenzenesulfonyl chloride and 5-chloro-2-nitrobenzenesulfonyl chloride were reacted with 2,6-dimethylaniline,respectively,to give the corresponding benzenesulfonamide derivatives.Reduction of the nitro group generated the 2-aminobenzenesulfonamides which were condensated with trimethyl orthoacetate to provide the corresponding 3-methyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives.After bromination of the 3-methyl group,the nucelophilic substitution of the resulting 3-bromomethyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives with the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine gave the respective iodide derivatives,which were further reacted with a series of arylboronic acids or borates via Suzuki coupling generated the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives Al-A10,B1-7,C1 and C2.In the preliminary PI3K? kinase inhibitory assay,most of the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited weak or no inhibitory activity.Only the 3,4-dimethoxyphenyl derivative A2,the indol-5-yl derivative A3 and the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amino derivative B1 showed relativel good inhibitory potency with the IC50 values 266,217 and 222 nM,respectively.In addition,the 2-methoxypridyl derivative A10 was moderate PI3K? inhibitor with an IC50 of 497.5 nM.The fluorine atom at the 7-position of 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide had a subtle influences on the PI3K8 inhibitory activity of these compounds,while the chlorine atom at the same position led to the lose of potency.In comparison with the quinazolinone lead compounds,the PI3K? inhibitory potency of these 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives was greatly reduced,possibly due to the decrease in hydrogen bondings with the affinity pocket.These results provided a basis for further inhibitors design and structural modifications. |
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