Design,Synthesis And Antiitumor Activity Testing Of Novel Inhibitors Based On The Structure Of AQP1

Background: All metabolism of tumors depends on the flow of water molecules through biofilms,and the fluid transfer intervened by aquaporins is the basic means by which water enters into and out of cells.Therefore,aquaporins can play an important role in tumor metastasis,development,and angiogenesis.effect.The main function of aquaporin 1（AQP1）is to transport water,and it is widely present in the human brain,spinal cord,kidney,liver,and colon.Studies have found that AQP1 is involved in the occurrence and development of various cancers and has become a tumor marker.Therefore,AQP1 plays an important role in the treatment and diagnosis of cancer.Inhibition of AQP1 can affect the migration,invasion and angiogenesis of tumor cells,but no specific inhibitor of AQP1 has been reported.The supervisor’s research group found from the previous work that the lead compound DAP-20 has a significant inhibitory effect on AQP1,and preliminarily summarized the structure-activity relationship of DAP-20 in the previous experiments,which laid the foundation for the synthesis of new AQP1 inhibitors.Objective: According to the specific hourglass water channel of AQP1,DAP-20 is used as the lead compound to further modify and transform,and it is expected to obtain target molecules with more contact sites and tighter binding with the inner pores of AQP1,which will provide new research ideas for the synthesis of AQP1 inhibitors.Methods: According to the structure of AQP1 and calculated by molecular modeling,five different routes were designed,and the lead compound DAP-20 was modified by chemical means such as click chemistry,cyclization and condensation.The antitumor activity was studied on the inhibition of the formation of human cervical cancer cells He La,human breast cancer cells MDA-MB-231,human prostate cancer cells PC-3,and human colon cancer cells HT-29.Results: Through 5 different design approaches,30 new sugar spiro-linked heterocyclic compounds were obtained.The structures were confirmed by 1H NMR,13 C NMR,MS,X-ray and IR,including series I compounds 5a-5q,series II compounds 6,7a,7b,series III compounds 13 a,13b,series IV compounds 16a-16 e,18,series V compounds 20 a,20b.Antitumor activity test found that compounds 5i（86.88% inhibition rate）,R-5l（85.68%）,5m（67.99%）and 7a（51.45%）showed significant inhibitory effect on colon cancer cell HT-29.Conclusion: AQP1 inhibitors have broad prospects as new anti-tumor inhibitors,our results demonstrate the design and provide new research ideas developing for cancer treatment.