Studies On Design, Synthesis And Anti-transthyretin Activities Of4H-1,4-Oxazines

Transthyretin (TTR) is a plasma transport protein and mainly transportsthyroxine (T4) and retinol binding protein in vivo. In the abnormal conditions ofphysiology or gene mutation, TTR tetramer dissociates and self-assemblies intoamyloid fibrils which deposit in human tissues to cause amyloid diseases. Theexisting experiments showed that the stabilization on the conformation of TTR couldinhibit its dissociation. By binding TTR, a great quantity of small molecules aredesigned and synthesized as drugs of amyloid diseases. In this paper, a novel TTRinhibitor--4H-1,4-oxazines is designed and synthesized based on the study on theinteractions between TTR and its inhibitors.TTR inhibitor--Structure design and virtual screening of4H-1,4-oxazines. Basedon the study on the interactions between TTR and its inhibitors by using astructure-based drug design approach,2,4,6-triaryl-4H-1,4-oxazines are confirmed asa potential TTR inhibitor. The52compounds of4H-1,4-oxazines are designedaccording to the basic structure of1,4-oxazines. By using AutoDock4.0, the52compounds are docked with TTR to predict their activities and the docking results areanalyzed in details.TTR inhibitor--Synthesis of4H-1,4-oxazines. The molecules of4H-1,4-oxazinesare selected as targets with a better predicting activity. The chosen4H-1,4-oxazinesare synthesized by the cyclodehydration of N,N-bis(phenacyl)anilines with POCl3.The N,N-bis(phenacyl)anilines are prepared from the corresponding phenacylbromides and anilines. In order to improve the reaction yields, the effects on thesynthesis of N,N-bis(phenacyl)anilines and2,4,6-triaryl-4H-1,4-oxazines are studiedin the synthetic methods, solvents, times and other factors.TTR inhibitor--Study on the activities of4H-1,4-oxazines. The synthesized4H-1,4-oxazines are tested to get their activities by using a method o f fibril formationassay. The results show that the synthesized4H-1,4-oxazines have obvious anti-TTRactivities.