| Part one:Pyrroloquinoline quinone(PQQ)is a kind of vitamins.It can be widely found in microorganisms,plants and animals.PQQ exhibits a variety of beneficial biological activities in vivo,and has a wide range of applications in food,medicine,agriculture and other fields.The human body cannot synthesize PQQ by itself,PQQ in human body is mainly derived from daily diet and intestinal microorganisms.There are two synthesis methods for PQQ:biosynthesis and chemical synthesis.Till now,the mechanism of PQQ biosynthesis has not been clarified,which brings difficulties to the directed evolution of biosynthetic pathways and the improvement of the production efficiency of PQQ biosynthesis.Total synthesis of PQQ has been studied for a long time,after a period of development,PQQ can be produced in large quantities by means of chemical synthesis.Compared with the biosynthesis method,the chemical synthesis method has many advantages,such as clear route,controllable reaction and high production efficiency.The chemical synthesis method is the main way to produce PQQ in large quantities now.The purpose of this study is to optimize the existing PQQ chemical synthesis process,simplify the process route,improve production efficiency,reduce environmental pollution,reduce production costs,enable current production processes to facilitate people to obtain PQQ more efficiently and safely.The total yield of the optimized process can reach 21%,which is dramatically higher than the original route yield(14%),and the reactions are safer and more suitable for mass production.In the optimized processes,atmospheric pressure hydrogen reduction is used to replace high-pressure hydrogen reduction,which avoids the production risks caused by high-pressure hydrogen and improves the safety of the production process.Optimizing the reaction conditions at each step to improve the yield of the reaction.The methods of purifying intermediates were investigated and optimized to simplify the purification method and reduce the loss in the purification process.Part two:Bile acids are formed in hepatocytes,and secreted into intestine to facilitate the absorption of dietary lipids,and are toxic to normal cells.Cholestasis is a disease that bile acids cannot be secreted as regular,accumulate in the liver and do harm to hepatocytes.Its etiology is diverse and complex.If left untreated,cholestasis can lead to severe liver disease.Farnesoid X receptor(FXR)is a receptor for bile acids,and regulates the expression of genes involved in bile acid metabolism but also genes regulating glucose and lipid metabolism and inflammation.Activation of FXR can promote the excretion of bile acids,limit the synthesis of bile acids,and thereby improve the symptoms of cholestasis.Oleanolic acid is a selective regulator of FXR,and has hepatoprotective effect at low concentrations.In order to make oleanolic acid derivatives have FXR agonist effect and enhance their selectivity,to obtain drug candidates with low toxicity and good efficacy.we designed a series of oleanolic acid derivatives according to the principle of active group splicing,introduced piperazine,fluorine and other groups into the structure of oleanolic acids.We synthesized 13 candidate derivatives,and their structures were confirmed.The activities of the derivatives are still being tested. |
