Synthesis Of Abexinostat And Research Of Novel Hydroxyquinoline Hydroxamic Acid Histone Deacetylase Inhibitors

At present,the main reason of human death is non-infectious diseases.After entering the 21st century,cancer is expected to become the first reason of death for human beings.Nowadays,epigenetics is closely related to the progression of tumor,and the modification of histones is one of the important phenomena of epigenetics.The level of acetylation of histones is regulated by histone acetyltransferase(HATs)and histone deacetylase(HDACs).HDAC is also involved in many other biological pathways such as cell signaling,cell growth,apoptosis,and so on.It is closely related to various types of cancer.Numerous studies have shown that HDAC inhibitors can synergize with existing radiotherapy or chemotherapy drugs to enhance anticancer effects.Five HDAC inhibitors have been approved for FDA and CFDA approval for cancer treatment.Abexinostat(PCI-24781)is a novel oral benzamide-type hydroxamic acid pan-histone deacetylase inhibitor developed by Xynomic Pharmaceuticals,Inc.Currently,phase III clinical trial of the first-line or second-line treatment of renal cell carcinoma(RCC)in combination with pazopanib was completed at South Korea.Also,the phase II and phase I clinical trials were performed on follicular cell tumor,solid tumor,diffuse large B-cell lymphoma and mantle cell lymphoma.This thesis mainly studies the synthesis process of Abexinostat.Firstly,through the analysis of the original research route reported in the literature and the structure of Abexinostat,the optimized procedure were determined.A new synthetic Abexinostat route was obtained by replacing the starting materials,investigating the reagents,and changing the strength of the alkali,finding the suitable work-up operations and purification methods for the factory treatment.The operation of the route was easier,the yield was improved,and the raw material cost of the reaction is significantly reduced.Compared with the original research route,the new route has the following advantages.First,the cost of the starting materials is reduced.Secondly,the work-up treatment method is optimized,and the column chromatography is replaced by acidification to precipitation,making it more suitable for industrial production.Finally,the purification method of the final product was optimized,and the purification method was replaced by recrystallization,which made it easier to use,and was suitable for constant or even large-scale purification,and was more suitable for industrial production.The total yield of this route is 3.5%,purity of the product is 97.2%.The second part is to synthesize a new group of histone deacetylase inhibitors based on the previous work of the our group and the structural characteristics of the hydroxamic acid histone deacetylase inhibitor.A preliminary bioactivity study was carried out on the target compounds to investigate the structure-activity relationship of quinoline hydroxamic acid type histone deacetylase inhibitors substituted at different positions.In our study,20 new compounds which include 10 intermediates and 10 targets were synthesized.All compounds were identified by 1H NMR,13C NMR and HR-MS.Among them,compound 19e showed better anti-proliferative activity against PC-3 cells compared with SAHA.After analysis of the structure-activity relationship of the compounds,it is considered that the 8-hydroxy-substituted quinoline as the Cap region and two carbons as Linker have the most favorable effect on the activity.