Research On The Synthesis Of Anti-apoptotic Protein Mcl-1 Inhibitor-obatoclax

Apoptosis is a programmed cell death mechanism and crucial for the maintenance of homeostasis.Once the mechanism is disordered,the organism will produce various diseases,such as cancer,autoimmune diseases,cardiovascular diseases,and neurodegenerative diseases.At present,there are three main apoptotic pathways:mitochondrial pathway,death receptor pathway and endoplasmic reticulum pathway.Among them,the mitochondrial pathway which is also known as intrinsic pathway is the most classic.Bcl-2 protein family plays an important role in the regulation of apoptosis through the protein-protein interaction(PPI).As far.25 members belong to Bcl-2 family have been confirmed?which can be divided into two categories according to their biological functions:anti-apoptotic proteins and pro-apoptotic proteins.Mel-1 protein belongs to the anti-apoptotic proteins.Studies have shown that the abnormal expression of Mcl-1 is associated with multiple tumor cell lines,and that Mel-1 is closely related to drug resistance of tumor cells.Therefore,in recent years,Mel-1 has become a new target for the development of anti-tumor drugs.Currently,the development of Mcl-1 inhibitors has achieved some results.Mel-1 inhibitors can divided into two broad categories:stapled-peptide mimics and small molecule inhibitors.There are more than 20 Mcl-1 small molecule inhibitors have been reported,which occupy the majority of Mcl-1 inhibitors.Obatoclax,also known as GX15-070,is an indole derivative based on the research of prodigiosin,which is developed by Gemin X.Experiments show that obatoclax can block the heterodimerization between anti-apoptotic protein and Bax/Bak,induce the cell apoptosis.The current clinical data shows that the efficacy of obatoclax in vivo is limited,however,there are still researchers exploring the anticancer activity of obatoclax in combination with other drugs as well as other pharmacological activities.In addition,obatoclax has a small molecular weight,which provides a broad structure optimization space for developing more active derivatives.In conclusion,obatoclax is still of high research value.This topic focuses on the synthesis of obatoclax.In the early stage,we synthesised obatoclax successfully by verifying the reported preparation route and made a lot of optimization work.In the later stage,a new synthesis route of obatoclax,which take advantages of Knoevenagel reactions,Vilsmiere-Haack reaction and Suzuki reaction,was successfully developed via several tests.We also optimized the material ratio,procedure,purification methods and so on to determine the better reaction conditions for each step of the new route.Compared with the reported method,the new synthesis route simplifies the experimental operation,improves the overall yield,and reduces the use of certain toxic substances.At present,the new preparation method is under patent application.