Studies On The Synthesis And Biological Function Of Polymethoxy,Prenyl And Amino Flavonoids

Flavonoids are an important active ingredient widely existing in medicinal plants,fruits,vegetables etc,which have a wide range of biological activities such as antioxidant,antibacterial,antitumor,cardiovascular and cerebrovascular.So as to enhance their physiological and pharmacological activities,solubility and biological conductivity,which is more conducive for absorption,the structure of flavonoids were modified.In this thesis,a series of polymethoxy,isopentenyl and amine flavonoids were synthesized by introducing methoxy,isopentenyl and amine groups based on the structure of flavonoids,and their antiproliferative activity or biological function was studied in vitro.1.A series of 5,6,7-trimethoxyflavonoids and their derivatives were synthesized using3,4,5-trimethoxyphenol as the starting material through Baeyer-Villiger oxidation,Fries rearrangement,Claisen-Schmidt condensation,ring-closing and regioselective demethylation.Nine of these compounds are natural products.The antiproliferative activity of the synthetic5,6,7-trimethoxyflavone compounds on human pancreatic cancer cells（Asp-1）,gastric cancer cells（SUN-5）,liver cancer cells（Hep G-2）and colon cancer cells（HCT-116）were tested by CTG cell viability assay using cisplatin as positive control.Among them,4,5-dihydroxy-3,5,6,7-tetramethoxyflavone（18）showed the highest antiproliferative activity(IC₅₀=5.30μM)in human pancreatic cancer.2.Eighteen natural and non-natural polymethoxyflavone derivatives were synthesized using naringin or hesperidin as starting materials,through glycosidic cleavage,dehydrogenation,selective methylation,bromination,nucleophilic aromatic substitution,O-isoprenylation,Claisen-Schmidt condensation,and cyclization oxidation.The antiproliferative activity of four human cancer cell lines,including pancreatic cancer cells（Aspc-1）,gastric cancer cells（SUN-5）,liver cancer cells（Hep G-2）and colon cancer cells（HCT-116）,were studied by CTG cell viability assay with cisplatin and stellin as positive controls.The results showed that some of the polymethoxy flavonoids synthesized exhibited moderatetogoodantiproliferativeactivity.Amongthem,2-hydroxy-3,4,5,5,6-pentamethoxy-3,4,4-methylenedioxychalcone（36）showed excellent inhibitory activity against all four tumor cell lines,and its antiproliferative activity against hepatoma cell lines(IC₅₀=10.35μM)was higher than that of the positive control drug cisplatin(IC₅₀=12.36μM).3.The natural products of 8-prenylflavonoids were synthesized from 2,4,6-trihydroxyacetophenone and 3,4-dimethoxybenzaldehyde by the steps of methoxymethyl protection,aldol condensation,oxidative cyclization with hydrogen peroxide,O-isopentenylation,Microwave catalyzed Claisen rearrangement,O-methylation and prentenyl side chain cyclization.8-isopentenylquercetin-3-methyl ether（49）,8-isopentenylquercetin-3,3’,4’,7-tetramethyl ether（53）and 8-isopentenyl quercetin（57）are three natural isoamentyl flavonoid compounds.4’’,4’’,5’’-trimethyl-5’’-H-tetrahydrofuran[2’’,3’’,5,6]quercetin（59）is a cycled derivative of the isopentenyl side chain.The mechanism of Claisen rearrangement in the synthesis of C-isopentenyl flavonoids from O-isopentenyl flavonoids under microwave catalysis was investigated.The microwave heating method can greatly shorten the reaction time of Claisen rearrangement with good regioselectivity and high yield.4.Based on the bioluminescence properties of amine flavonoids,an HSA-specific binding fluorescent molecule 2-（4-（diethylamino）phenyl）-3-（（4-methylquinazolin-2-yl）methoxy）-4H-chromene-4-one（FNE3）was synthesized.The fluorescent molecule has good sensitivity and specificity for HSA,with a 1042-fold fluorescence enhancement reaction.The binding affinity to HSA was high with binding constant（K_b）of FNE3 and HSA was 7.71×105M^-1.A FNE3-HSA composite fluorescence sensor was successfully designed and applied for the first time to the intracellular imaging study of the non-steroidal anti-inflammatory drug diflunisal in urine and plasma.The detection concentration range was 1-150μM,and the minimum detection limit was 3.99μM（0.99 mg/L）.The FNE3-HSA complex platform showed good stability,sensitivity and high selectivity.