Design And Synthesis Of AND-1 Inhibitors And Its Photoaffinity Probe

Objective:Human acidic nucleoplasmic DNA-binding protein 1(AND-1),highly expressed in a variety of tumor cell models,is essential for homologous recombination(HR)repair as a new target in recent years.In tumor cells,AND-1 dysfunction effectively inhibits DNA damage repair which promotes tumor cell death.Furthermore,DNA damage repair is one of the main causes of resistance to some anticancer drugs(such as cisplatin).Therefore,AND-1 is a potential target for the treatment of cancer,and the discovery of its inhibitors may provide a new direction for the treatment of cancer and the solution of drug resistance problems.While photoaffinity probe technology can provide reliable guidance information for drug design by determining the specific binding effects of small molecule compounds with known target proteins.Methods:Based on the active lead compound bazedoxifene,this subject designed and synthesized novel AND-1 inhibitors with the help of computer aided drug design and bioelectronics isosteric methods.The compounds were characterized by nuclear magnetic resonance and mass spectrometry to confirm the structure.Bioactivity evaluation used Western Blot assay to observe the inhibitory effect of each compound on the expression of AND-1 in MCF-7 cells.After the structure-activity relationship was established by molecular dynamics simulation,the photoaffinity probe was designed,synthesized,and evaluated.Results:This article designed and synthesized a series of target compounds targeting AND-1,including a photoaffinity probe,altogether 24 small molecules,to establish the preliminary structure-activity relationship of these compounds.The inhibitory rate of compound 12b on AND-1 reached 67%at 10 μM in MCF-7 cells,superior to 46%of the lead compound,and the inhibitory rate of the photoaffinity probe 21 reached 67%at 10μM with 40 min as its optimum radiation duration.Conclusion:The research investigated the structure-activity relationship between 2-arylindoles and AND-1,and provided an effective photoaffinity probe,which can help to analyze the specific binding mode of small molecule compounds and AND-1 at the molecular level,and guide the design of AND-1 inhibitors to promote the development of new cancer treatment drugs.