Design,Synthesis And Structure-activity Relationship Of Novel Naphthoquinone Analogs Targeting Wnt/?-cateinln/TCF Pathway

The new molecular targeted therapy is imminent because of limitations of the current application of chemotherapy and radiotherapy of cancer.The Wnt/?-cateinin/TCF signaling pathway plays a critical role in the initiation and progression of cancer,especially colorectal cancer.As the identification of crystalline structures of ?-catenin complexed with TCFs,the small molecule inhibitors targeting the signaling pathway have attracted more attention recently.According to the crystal structure of ?-cateinin/TCF complex and the structure of small molecule inhibitors of ?-cateinin/TCF,a series of novel naphthoquinone derivatives were designed and synthesized.The naphthoquinone derivatives were synthesized by nucleophilic substitution reactions with different substituent sulfonyl chlorides and amino groups to obtain different sulfonamide group side chains,which were then coupled with a naphthoquinone mother nucleus.39 naphthoquinone derivatives were obtained,in which 27 compounds.were novel.The structures of all key intermediates and target products have been confirmed by 1H-NMR,13C-NMR and LC/MS.The synthesized compounds were evaluated for the inhibitory activity of ?-cateinin overpressing human colon cancer cells SW480 and HCT116.Compound 1f?1p and 4f showed the higher inhibitory activity.The analysis of structure-activity relationship revealed that the change of substituents in the terminal region of the side chain had a greater influence on the activity.The ?-cateinin/TCF complex has a hydrophobic pocket which can accommodate a certain spatial structure.The activity increased if the ends of the side chains were bulky and hydrogen bonds were available.The sulfonamide groups were essential groups because the activity decreased with changing sulfonamide group into the sulfamoyl group.Chlorine at C-3 of the naphthoquinone is an essential group for the activity.The introduction of an electronwithdrawing group at the C-6 position slightly improves the activity,but the activity of introducing an electron-donating group decreases significantly.The introduction of an electron-withdrawing or electron donating group at the C-5 position leads to a decrease in activity.In addition,compound 1f?1p and 4f exhibited improving lipid-water partition coefficient.In conclusion,the synthesis and activity of four series of novel naphthoquinone derivatives were studied,and identified a compound 1f?1p and 4f with potent inhibitory activity,which laid a foundation for the discovery of this kind of new drugs.