| Natural products are important sources of drug development,chromones are widely found in plants and have a variety of biological activities.Chromone is an important structural skeleton of medicinal chemistry.New drug molecules can be obtained by synthesis and modification of chromones.The research contents of this thesis include:（1）Total synthesis and glycosidation modification of the natural product eucryphin;（2）Synthesis of eucryphin analogues,noreugenin glycosides;（3）Synthesis of noreugenin C-3 aminopyridine derivatives by the principle of drug combination;（4）Study the anti-inflammatory activity in vivo and structure-activity relationship of synthesized compounds.1.Chemical synthesis of targets（1）Total synthesis of natural product eucryphin and its glycoside derivativesUsing cheap phloroglucinol as starting material,the natural product eucryphin was obtained by 7 steps,including Friedel-Crafts acylation,Vilsmeyer-Hack reaction,hydroxyl protection and deprotection,selective oxidation,and glycosidation,with a total yield of 5.8%.The C-7hydroxyl group of eucryphin was modified by glycosidation,and the glycosyl donors included rhamnose,glucose,mannose,galactose and arabinose.Five eucryphin C-7 derivatives were obtained by phase transfer catalysis and Schmidt glycosidation with the total yield of 3.5-3.9%.（2）Noreugenin glycosidesFive noreugenin glycosides,including rhamnoside,glucoside,mannoside,galactoside and arabinoside,were obtained by 8 steps of Friedel-Crafts acylation,Kostanecki-Robinson reaction,ester hydrolysis,hydroxyl protection and deprotection,and glycosidation.The total yield was 11.6-12.8%.（3）Noreugenin C-3 aminopyridine derivativesThe intermediate with carboxyl functional arm and aminopyridine were condensed and the benzyl protective group was removed to obtain noreugenin C-3 aminopyridine derivatives with the total yield of 7.4-8.6%.Five noreugenin C-3 aminopyridine derivatives included 2-amino-4-methylpyridine,2-amino-4-ethylpyridine,2-amino-4-methoxypyridine and 2-amino-4-fluopyridine.The structures of all the synthesized compounds were confirmed by 1H NMR,13C NMR and HRMS.2.Pharmacological experimentThe DNFB-induced mouse ear edema model was used to evaluate the inhibitory effect of synthetic compounds on chronic inflammation by the mouse ear swelling rate,thymus index,spleen weight index,and TNF-α,IL-10,IL-6 and IL-1βlevels in mouse plasma.The results indicated that eucryphin,EC8d,EC8e,NE8c,NE8d,NE8e,NE12a and NE12b showed moderate inhibitory activity on ear swelling in mice,which were slightly worse than dexamethasone.Eucryphin,EC8d,NE12a and NE12b can effectively reduce the levels of NO,TNF-α,IL-1βand IL-6.According to the results of spleen index and thymus index,compared with dexamethasone,the synthesized compound had lower toxicity and could be taken for a long time.3.Research on the structure-activity relationship（1）Noreugenin modified by rhamnose and glucosyl can improve pharmacological activity;（2）The activity of noreugenin-rhamnoside was better than other glycosyl substitutions;（3）eucryphin has excellent effect and the presence of C-2 methyl group may be detrimental to pharmacological activity;（4）eucryphin glycoside derivatives are not as effective as the parent eucryphin,the C-7 hydroxyl group may be one of the key to activity;（5）The effect of noreugenin-aminopyridine hybrids was better than noreugenin,which may be related to the decrease in the level of pro-inflammatory factors;（6）C-4 methyl substituted derivatives of 2-aminopyridine are superior to ethyl,methoxy,fluorine substituted and unsubstituted derivatives. |
