The Design Synthesis And SAR Of Phenanthridine Wnt Signaling Agonist

The Wnt/?-catenin signaling pathway,a highly conservative signal transduction pathway in vertebrates,regulated numerous life processes.The abnormality of Wnt signaling pathway can lead to normal physiological dysfunction of the human body and resulted in the occurrence of various diseases,such as cancers,cardiovascular disease and osteoporosis.Appropriate interventions in the abnormal Wnt signaling pathway were used to treat some clinical diseases.At present,most studies focus on the discovery of Wnt inhibitors to treat cancers.But there are fewer studies on agonists and only a small number of small chemical molecules have been reported to activate the Wnt signaling pathway.Our reseach team found that a specific agonist could regulate Wnt/?-catenin signaling pathway.It was a derivative of Lycorine by Hoffman elimination reaction and equiped with research value for the treatment of leukemia and osteoporosis.However,it not suitable as a Wnt signaling pathway agonist drug molecule due to the low activity of HLY78.Therefore,this dissertation will combine the relevant research results to design and synthesize new phenanthridine-type Wnt signaling pathway agonists.In the first chapter,we introduces the HLY78 derivatives' research and the types of phenyridine alkaloids.In the second chapter,we analyzes the structure-activity relationship of HLY78 derivatives and designed three kinds of compounds,such as C-4 oxysubstituted group phenanthridine,1,4 dibromobutane connected simple dimer and dimers connected by triazole groups by molecular docking simulation.What's more,we designed reaction routes,reaction conditions and substrates for the synthesis of C-4 oxysubstituted group phenanthridine and determined the routes and conditions of 1,4 dibromobutane connected simple dimer and dimers connected by triazole groups.We tried to synthesis carbon-carbon coupling dimers by Ullman reaction and Suzuki reaction.The third chapter is about the synthesis of these compounds.And 78 compounds were synthesized,such as twenty-two C-4 oxysubstituted group phenanthridines,twelve C-4 vinyl phenanthridines,twenty-five C-4 alkyl substituted group phenanthridine intermediates,twelve 1,4 dibromobutane-connected dimers and seven triazole-connected dimers.The fourth chapter introduces the activitives of these dimers and analyses the relationship between activitives and structures of phenanthridine dimers.The resultes show that 1,4 dibromobutane dimers have a weak agonist activity in the Wnt/?-catenin signaling pathway and all triazole-connected dimers exhibit inhibitory activity in the Wnt/?-catenin signal.Besides C-4 ethyl phenanthridine dimers connected by 1,4 dibromobutane have a better activity than C-4 methyl phenanthridine dimers.We also found that the dimers connected by 1,4 dibromobutane lose the activity of Wnt/?-catenin signaling pathway when two monomers can't active Wnt/?-catenin signaling pathway.In addition,the activitives of triazole-connected dimers have little link to the monomers' activitives and they completely show inhibitor activitives to Wnt/?-catenin signaling pathway.