Synthesis And Preliminary Biological Activity Evaluation Of Lactam Chemical Constituents And Their Derivatives Extracted From Clausena Lansium(lour.) Skeels

In this paper,the biological activity and synthetic method of amide in wampee was studied.In particular,the synthesis of?-substituted epoxypropionate,a key chiral intermediate in its asymmetric synthesis method,is reviewed in detail.On this basis,two aspects of work mainly researched,the specific research as follows:1.Optimization of synthetic route for?+?-norbalasubramide derivatives of trifluoromethylphenyl groups.In previous study of series derivatives of?+?-Norbalasubramide from natural product?+?-balasubramide,6-p-trifluoromethylphenyl-substituted?+?-Norbalasubra mide with a certain inhibitory effect on the release of BV-2 microglia inflamm atory factor TNF?from lipopolysaccharide has be found.But the overall yield is low.A synthetic process with simpler operation and higher yield should be established.In order to provide samples for pharmacological experiments,the r eaction solvent,feeding sequence and choice of catalyst were optimized on the basis of original synthetic route.Compound 3 was obtained by Wittig reaction with triphenylphosphine?1?as the initial reactant.Followed by reaction with p-trifluoromethylbenzaldehyde?4?to prepare p-trifluoromethyl cinnamic aldehyde?5?.By improving the post-treatment method,from a single column chromatograph y to column chromatography and recrystallization,can quickly get numerous th e product and save costs;Then,according to the method of Xuan Yining^[70],T he intermediate 10a was obtained by compound 5 via"one pot"organocatalytic epoxidation and oxidative esterification with chiral catalyst 8a.Through the st udy of the reaction mechanism CH₃OH>NBS>Na₂CO₃ was the optimum feeding sequence in this step;The highest yield of chain amides,formed by intermedi ate 10a and tryptamine,was 91.2%with potassium tert-butoxide as the basic c atalyst.Finally,the chain amide was catalyzed by trifluoroethane sulfonated ytt erbium,and intramolecular cyclization occurred in acetonitrile in a yield of 73%and the ee value of 96%.The overall yield is increased from 44.3%to 56.5%?Calculated with compound 5?with the simpler optimized synthesis proces s.In this paper,the left-handed intermediates 10b and 12b were also prepared using a chiral puromone-based catalyst of the opposite configuration.Cyclizatio n end products are not optically active,indicating that the reaction process ma y occur racemization.Therefore,it is desirable to obtain 6-p-trifluoromethylphe nyl-substituted?-?-norbalasubramide with screening other chiral catalysts or ch anging the reaction conditions.Work in this area has yet to be further improve d.2.Synthesis and Bioactivity Evaluation of Racemic?-Ester Substituted?-Lactam Compounds.Under the Reference^[12,30],clausenamide and other?-lactam compounds have a certain anti-Alzheimer's and other pharmacological effects.In order to improve their fat-soluble,7 ester-substituted derivatives were synthesized and determined inhibitory activity against Caspase-3 and PTP?because of their poor fat-soluble,low lipid-water partition coefficient,resulting in low cell permeability.In this paper,the two?-lactam compounds with 3,4-cis-substituents are synthesized by the method of Literature^[100].And 7 ester derivatives were prepared by using these two compounds as raw materials with acid chloride and isocyanate as acylating reagents?15a-15c,16a-16d?.The acylating agent is changed so that the reaction is simple and the risk is reduced.PTP?and Caspase-3 were obtained by isolation and purification under appropriate conditions through the Escherichia coli expression system.The inhibitory activity of 7derivatives on Caspase-3 and PTP?was tested respectively.The highest inhibition rate of Caspase-3 in 7 compounds was 34%?16b?,but still did not reach the effective inhibition rate.The inhibition rate of PTP?by 7 derivatives was less than 10%.From the inhibition results of Caspase-3 and PTP?,it can be seen that the?-esterification-substituted derivatives of racemates have lower inhibitory activity on Caspase-3 and PTP?,indicating their lack of further research in the treatment of neurodegenerative diseases.Therefore,by simply esterifying hydroxyl groups to improve cell permeability in order to improve the biological activity of the method remains to be further explored.