Synthesis And Biological Activity Study On Imidazo[4,5-c]Quinoline Derivatives

In recent years,through the study of phosphatidylinostitol 3-kinase(PI3K)/v-akt murine thymoma viral oncogene nomolog(AKT)/mammalian target of rapamycin(m TOR)signal transduction pathway,we can find that it plays an important role in the processes of lung cancer,urinary system and digestive system cancer diseases,has become one of the hot points in present research.Due to the disordered ability of PTEN gene or activated by other signals,the activation of PI3K/AKT/m TOR signal transduction pathway can lead to the cell apoptosis is restrained,the cell cycle running faster and promoting angiogenesis,tumor invasion and metastasis,so it plays an important role in the occurrence and development of tumor.Our lab team members have drew on the small-molecule inhibitor NVP-BEZ235 which has target effect on PI3K/AKT/m TOR signal transduction pathway,because the imidazoquinoline skeleton of NVP-BEZ235 is considered to be a special kind of ATP specific binding site kinase inhibitors and then we can accord to the structure-activity relationship for the development of new drugs.Therefore,in order to find efficient and low toxicity of antineoplastic candidate compounds,our lab team members chose Imidazo[4,5-c]quinoline compound BEZ-235 as lead compound after sufficient literature research,based on the principle of inverse synthetic analysis method to split the skeleton of the target compounds,introduced different substituents at 8 position to obtain three imidazo[4,5-c]quinoline derivatives via substitution,reduction,cyclization,methylation and Suzuki reaction.The structures of the key intermediate and target compounds obtained in the process of synthetic experiment were confirmed by 1H NMR,13 C NMR and HRMS.We have been also mensurated antitumor activity in vitro of target compounds by m TOR kinase activity test and PI3K-alpha enzyme activity test.The experiments indicated that target compounds 12a~12c have certain inhibitory effect on m TOR protease and PI3 K kinase,respectively.Compounds 12 b,12c in particular displayed the m TOR protease inhibitory effect on m TOR;Compounds 12 a,12b,in particular displayed the PI3 K kinase inhibitory effect on PI3 K.Compound 12 b in particular displayed the strongest activities both on PI3K?/m TOR.