Design, Synthesis And Anti-inflammatory Activity Of Linalool And Its Derivative

The Asteraceae plant Blumea balsamifera is one of the important traditional Chinese medicinal materials,its active components displayed anti-inflammatory,anti-tumor,anti-fungal,free radical scavenging,anti-obesity and other physiological activities.Blumeatin extracted from the plant has been proved to have certain anti-inflammatory activity,which is a flavanone compound different from traditional non-steroidal anti-inflammatory drugs（NSAID）.However,due to its shortcomings such as single source,complex extraction process and low yield,it is difficult and expensive to obtain blumeatin,which is detrimental to subsequent biological research.However,there was no synthetic approach to obtain optically active blumeatin,so it is necessary to construct a synthetic procedure for blumeatin preparation.In this paper,2,4,6-trihydroxyacetophenone was used as raw material.After methylation and cyclization,the racemic blumeatin could be obtained.Then,the optically active products（R）-5-hydroxy-7-methoxy-2-（3,5-dihydroxyphenyl）benzodipyrane-4-one（1A）and（S）-5-hydroxy-7-methoxy-2-（3,5-dihydroxyphenyl）benzodipyrane-4-one（1B）were obtained via three consecutive steps:an imimization process of the racemic blumeatin with a chiral agent of（S）-（-）-α-methylbenzylamine,a separation process by chromatographic column and a hydrolysis process.The structure of 1B was consistent with the putative structure of blumeatin,and the synthetic procedure had a total yield of about 20%.Compared with the process extracted from plants,the efficiency of blumeatin preparation was significantly improved.In addition,the absolute configurations of 1A and 1B were determined by the specific optical rotation and electronic circular dichroism（ECD）data.Intriguingly,the result of synthetic blumeatin was not consistent with that of extracted blumeatin（commercially available）in a TLC experiment.The inconssitency was further confirmed by HPLC data.After literature review,it was found that the reported structural data of blumeatin was confused.Therefore,the structure of synthesized blumeatin（1）and extracted blumeatin（4A）was systematically compared and analyzed by means of ¹H-NMR,¹³C-NMR,HMBC,HSQC data and melting point values.Combined with the rigorous logic of the synthesis process of blumeatin,compound 1 was consistent with the putative structure of blumeatin,and the structure of"blumeatin"obtained by the extraction process should be corrected to be（S）-5-hydroxy-7-methoxy-2-（3,4-dihydroxyphenyl）benzodihydropyrane-4-one.Simultaneously,5-hydroxy-7-methoxy-2-（3,4-dihydroxyphenyl）benzodihydropyrano-4-one（4）was synthesized by replacing the substrate aldehyde,and the TLC,HPLC and NMR data of 4 were consistent with 4A.The anti-inflammatory activity of compound 1 was tested by ear swelling experiments in mice,with dexamethasone as positive control.The inhibitory rates of compound 1 was 38.17%,40.66%and 48.70%at low（7.5 mg/kg）,medium（15 mg/kg）and high（30 mg/kg）doses,respectively.The counterparts of 4A were 27.74%,66.13%and 73.53,respectively,and 9.79%,26.58%and 54.52%for compound 4.The results indicated that 4A had the best anti-inflammatory activity（about 1/3 of the positive drug dexamethasone）,the anti-inflammatory activity of optically pure 4A was more potent than than that of racemate 4,and the compound with 3’,4’-dihydroxyl at B ring 3’,4’-dihydroxyl had better anti-inflammatory activity than 3’,5’-dihydroxyl substituted compound.The slow-reacting substance SRS-A inhibition assay showed that the activity of 1A and 1B was equivalent to that of the positive control ketotifen,and the inhibition rate were more than 40%,while the corresponding activities of 4P and 4Q were relatively weak.Hydrophobic groups were introduced on the hydroxyl group of ring B to synthesize 11 blumeatin derivatives,all of which had no obvious anti-inflammatory activity.