The Synthesis,Structure Modification And Biological Activity Of Vibralactone And Other Three Natural Products

This thesis mainly studies the synthesis of vibralactone derivatives and three active natural products:(?)Structural modification and biological activity of Vibralactone has been researched;(?)The Trogia sp.toxin(2R,4S)-2-amino-4-hydroxyhex-5-ynoic acid(139)has been totally synthesized;(?)Biomimetic synthesis of windmill-shaped molecule(±)-Linderaspirone A(167)and(±)-Bi-linderone(168)has been achieved and explored its reaction mechanism;(?)Biological activity and biomimetic synthetic research on(±)-Guajadial B(170)has been studied.(?)Some of ether bond Vibralactone derivatives and some ester bond Vibralactone derivatives were synthesized through structural modification of the ?-hydroxy group of the Vibralactone.Biological activity showed ester bond of Vibralactone derivatives can enhance activity.Therefore,we first synthesized 60 Vibralactone derivatives with an ester bond,which the ? side-chain groups included saturated fatty acid,unsaturated fatty acid,aromatics with long chain fatty acid groups,heterocyclic compounds with long-chain fatty acid,long chain fatty di-acids,the formyl amino acid.These Vibralactone esters were tested the inhibition of pancreatic lipase,and we found a phenyl group with the four carbon fatty acid Vibralactone derivative biologically active of one order of magnitude lower than Orlistat.Based on these biological activities we used computer simulation software Discovery Studio(DS)and PyMOL computer simulation.Computational simulation results showed that on Vibralactone ?position connecting the two groups with the appropriate length fatty acid groups will be more conducive to the improvement of the activity.So in the subsequent work we followed this instruction.In the first method,the Vibralactone ?-hydroxy was oxidized to the aldehyde,then the aldehyde reacted with the Grignard reaction,generating secondary alcohol,and after the secondary alcohol was connected with the appropriate length fatty acids or amino acid groups,an ester bond with two side-chain derivatives was formed.In the second method,the Vibralactone ?-hydroxy was oxidized into the acid by the Jones reagent,then the Vibralactone acid reacted with the di-amine to form amide derivatives under the EDCI existence.In the latter activity tests,we found many Vibralactone derivatives.When we compared its pancreatic lipase inhibitory activity with the prototype compound(Vibralactone),we found IC50 values of the Vibralactone derivatives decreased three orders of magnitude,reaching nanomolar level.Those compounds had the similar efficacy group and mechanism with commercially available OTC drug Orlistat.For these reasons,we never stopped searching for natural products from cultures of the basidiomycete B.vibrans.,and 21 compounds,including 10 news compounds,were isolated from the above mentioned species with various chromatographic methods,and their structures were established on the basis of extensive spectroscopic analysis(including 1D and 2D NMR,MS,HR-MS,IR).The class of these new compounds included sesquiterpenes,triterpenoids,phthalide derivatives,etc.The new compounds displayed no significant cytotoxicities against HL-60,SMMC-7721,A-549,MCF-7 and SW-480 five human cancer cell lines(IC50>40 ?M).(?)The Trogia sp.toxin(2R,4S)-2-amino-4-hydroxyhex-5-ynoic acid(139)was totally synthesized through the amidation reaction,Grignard reaction and asymmetric CBS catalytic hydrogenation with an overall yield of 46%.The absolute configuration of natural product 139 was determined as 2R,4S configuration by comparing the optical rotation.Compound 139 was suggested as 2R-amino-4S-hydroxy-5-hexy-noic acid.In the acute toxicity test experiment to mice,the measured compounds 139 and 140 of the median lethal dose(LD50)values were 70.7 and 83.8 mg/kg.In the Further investigation,mice administered 139 and 140 from Trogia sp.exhibiting a 1.1-1.6 fold increase in serum creatine kinase(CK)activity compared to controls which received water,and this was the main cause of death of the mice.There was no activity in experimentally induced neuronal differentiation(PC 12 cells).(?)Under the AIBN existence condition,a one-step biomimetic synthesis of(±)-linderaspirone A(167)and(±)-bi-linderone(168)from the Methyllinderone(166)has been achieved,which probably reflects the biosynthesis of the natural products.There are few naturally occurring substances that appear to be formed by a[4+4]or[4+2]cycloaddition.We proposed that the[4+4]dimerization of methyllinderone proceeds via a stepwise mechanism involving a diradical intermediate.(?)The(±)-Guajadial B(170)was biomimetic synthesized in a domino three-component coupling reaction with an overall yield of 45%.Studying the reaction conditions,we found that the reaction in NaOAc-AcOH system had a good yield.Then we performed 11?-HSD1 and cytotoxic activity screening experiments on compound 170.Experiments indicated that the 170 had no significant inhibition on mouse and human 11?-HSD1,but it had a certain HL-60,SMMC-7721,A-549,MCF-7 and SW-480 in five different human tumor cell inhibitory activities.