Study On The Structural Optimization And Anti-Tumor Activity Of A New Type Of AQP1 Inhibitor

Background:Aquaporin 1（AQP1）is a hydrophobic transmembrane protein located on the cell membrane and plays a major role in the transcellular transport of water.More and more studies have shown that the overexpression of AQP1 is related to many types of cancer,such as brain tumor,lung cancer,liver cancer,colorectal cancer,breast cancer,etc.,and confirmed that AQP1 is involved in tumor cell proliferation,migration,invasion and tumor blood vessels,and plays an important regulatory role in the process of generation.Therefore,the inhibitor study targeting on AQP1 as a tumor biomarker will provide new directions and approaches for the discovery of new anti-tumor drugs and tumor targeted therapy.However,the application of AQP1inhibitors for tumor treatment has not been reported so far.Based on the structure of AQP1,my supervisor’s group designed and synthesized a series of glycoheterocyclic compounds with different structures in the previous work.The anti-tumor activity screening found that DAP-20 showed significant lung cancer inhibitory activity;Western Blot analysis results showed that DAP-20 has a significant inhibitory effect on AQP1;molecular model calculations show that DAP-20 can dock with AQP1 to prove the interaction.Objective:Using DAP-20 as the lead compound,the structure was further optimized by synthesis of a series of analogs in order to screen novel compounds for strong inhibitory effects on tumor cell proliferation,migration/metastasis,invasion and angiogenesis,and develop the potential for applying to clinical application opening up a new path for in-depth research on new anti-tumor drugs.Methods:Based on the structure of DAP-20,we plan to synthesize a series of novel analogs by introducing various sizes and properties substituent groups at different positions of the 5-phenyl ring,or replacing 5-phenyl ring with diverse herterocyclic systems.Then,to test the activities on four tumor cell lines:MDA-MB-231,PC3,HT-29,and Hela through the CCK8 method.Results:Based on the series of synthesis,separation,purification,there are more than 120 compounds were obtained,in which 116 were novel molecules,and 58 were DAP-20 analogs.Their structures were analyzed and confirmed by ¹H,¹³C-NMR,COSY,NOESY,elementary analysis,X-ray single crystal diffraction data.The activity test results showed that different compounds have different inhibition on tumor cells.Conclusion:The corresponding relationship between the target molecular structure and anti-tumor activity confirms the design idea of our new inhibitors based on AQP1structure,and provides the basis and help for further optimizing the structure,improving the anti-tumor activity and inhibiting the expression of AQP1.