Studies On The Synthesis And Bioactivity Of Natural And Non-natural Prenylated And Polymethoxyl Flavonoids

Flavonoids are phenolic secondary metabolites which are widely distributed throughout the plant kingdom.They were isolated from various plants,and are a class of importance natural products.These compounds have a variety of biological activities and potent medical applications,such as anti-tumor and anti-cancer activity,antibacterial and antiviral activity,anti-cardiovascular disease,enzyme inhibitory activity,anti-free radical and antioxidant activity,etc.Prenylated flavonoids are a unique class of naturally occurring flavonoids characterised by the presence of a prenylated side chain on the flavonoid skeleton.C-prenylation of flavonoids can enhance binding affinity toward p-glycoprotein and increase ability to permeate cell membranes,which can significantly improve the biological activity of flavonoids.Thus,prenylated flavonoids show promise as lead compounds for the development of nutraceuticals and pharmacologiceutics in plants and new agents for the treatment of human diseases.Polymethoxyflavonoids are a family of the natural compounds in citrus fruits.PMFs have shown various biological functions.PMFs and their hydroxylated derivatives have been proven to be potent therapeutic agents in p reventing diseases,such as chronic inflammation,tumor development,atherosclerosis,thrombosis,and oxidation damage.Multiple methoxyl groups on the structure of PMFs contribute to their highly hydrophobic nature,which results in a low aqueous solubili ty and poor oral bioavailability.The application of an emulsion-based delivery technology has been investigated for PMF oral ingestion with the interest of improving its bioavailability.Naturally occurring prenylflavonoids and polymethoxy flavonoids are limited by the low contents in the plants kingdom,which they were negatively influenced their further bioactivity evaluation.Therefore,chemical synthesis of flavonoids and prenylflavonoid will be a very important alternative approach for addressing the problem of its availability.In this thesis,the synthesis and bioactivity of natural or non-natural polymethoxyl and prenylated flavonoids based derivatives have been studied.1.Twenty prenylated flavonoids 1-20 were synthesized using glycoside hydrolysis,dehydrogenation,selective O-methylation,O-prenylation and Claisen rearrangement reaction,from abundant and inexpensive natural flavonoids naringin,hesperidin,quercetin and myricetin.Among them,1-7,10-15 and 17-20 are novel compounds,the natural product 3,3′,4′,7-tetramethoxy-8-prenyl-5-hydroxy flavonoid（16）was first synthesized in high yield.Their antiproliferative activities were evaluated in vitro on a panel of three human cancer cell lines（Hela,HCC1954 and SK-OV-3）.The results showed that most of target compounds displayed moderate to potent antiproliferative activities against the three cancer cells with IC ₅₀ values from0.49 to 95.07μΜ.Among them,3′,4′,7-trimethoxyl-5-hydroxyl-8-prenyl flavonoid（12）exhibited the strongest antiprolirative activity on the three cancer cells mentioned above with IC₅₀ values of 0.91-7.08μΜ.3′,7-Dimethoxy-5-O-prenyl flavone（6）and3′,4′,7-trimethoxy-5-O-prenyl flavone（10）showed selective antiproliferative activity against HCC1954 cells with IC₅₀ value of 0.49 and 5.32μΜrespectively.2.Two series of polymethoxychalcones and polymethoxyflavones,including t h e natural products 2′-h yd r o x y-3,4,5,4′,6′-p e n t a m e t h o x yc h a l c o n e（2 8 c）,5,6,7,8,3′,4′,5′-heptamethoxyflavone（26）,5,7,3′,4′,5′-pentamethoxyflavone（29c）,and3-hydroxy-5,6,7,8,3′,4′,5′-heptamethoxyflavone（27）were synthesized by bromination,methoxylation,Ulmann-type reaction,and dimethyldioxirane（DMDO）oxidation,from commercially available 1,3-dimethoxybenzene as a starting material.Antiproliferative activity in vitro was evaluated against a panel of three human cancer cell lines（Hela,HCC 1954 and SK-OV-3）by cell counting kit-8（CCK-8）assay.The results showed that most of synthetic compounds exhibited moderate to potent antiproliferative activities.Some compounds displayed equal or higher potential than the positive control drug cis-Platin.In particular,compounds 24c,24e,28a,and 29a possess the IC₅₀0 equal or below 10μM,and worthy of further investigation.3.A series of polymethoxyflavonoids 41-60 were synthesized through dehydrogenation,O-methylation,glycoside hydrolysis,bromination,microwave-assisted aromatic nucleophilic substitution,dimethyldioxirane（DMDO）oxidation and regioselective demethylation,starting from abundant and inexpensive natural sources naringin and hesperidin.All the synthetic compounds were test ed for antiproliferative activities on human cervical carcinoma Hela cell line by the standard CCK-8 assay,the result showed that most of the target compounds exhibited moderat e to potent antiproliferative activities on Hela cells comparable with the positive control cis-Platin.Among them,5-hydroxypolymethoxy flavonoid 59 showed the strongest activity(IC₅₀0.791μM).