Synthesis And Bioactivity Of Polymethoxyfavonoids And Their O-glycoside Derivatives

Polymethoxyfavonoids (PMFs), which widely exist in citrus plants, possessexcellent anticarcinogenic and antiinfalmmatory activities, including antiviral,antioxidant, anticarcinogenic, antitithrombogenic and so on. Despite of many recentreports in PMFs and their biological activities, synthesiz of these compounds havebeen much less studied. Thus, we turned to the semisynthetic method starting fromreadily available natural source.1) We reported the facile synthesis of a series of polymethoxyflavonoids (1-12)with good yields from abundant and inexpensive natural sources naringin andhesperidin, which are the predominant flavonoids in sweet orange. Synthesiz of aseries of polymethoxyflavonoids1-12were performed via reactions of glycosidehydrolysis, dehydrogenation, bromination, Ullmann aromatic nucleophilicsubstitution, O-methylation, dimethyldioxirane (DMDO) oxidation and regioselectivedemethylation. The new synthetic route had the advantages of easy availability ofstarting materials, simple operation and good yields, so it had considerable andpractical value.2) The key step was Ullmann nucleophilic substitution reaction in this paper.Microwave-assisted reaction was firstly led in the Ullmann reaction. The optimizedreaction conditions: the microwave power was700W, the catalyst was5%CuBr, andthe reaction temperature was120oC. The highest yields could reach90%and thereacting time was1h. We discussed the ressonable Ullmann mechanism.3) The study of flavonols synthesis was carried out. DMDO oxidation thatflavones transformed to flavonols was efficiently improved, potassium hydrogensulfate solution was added to acetone intermittently, it made the new generation ofperoxide acetone directly to react with materials, the reaction was at roomtemperature, and the yields could been67%.4)5,6,7,8,4′-pendamethoxyflavone-3-O-β-D-glucosides and5,6,7,8,3′,4′-hexa-methoxyflavone-3-O-β-D-glucosides were from3-hydroxy-5,6,7,8,4′-pendamethoxy-flavone and3-hydroxy-5,6,7,8,3′,4′-hexamethoxyflavone, via by the reactionsincluding acetylization, bromidation, glycosidation and deprotection with thecorresponding-acetylglycosyl bromide respectively. Synthesis8flavone-3-O-β-D-glucosides such as5,6,7,8,3′,4′-hexamethoxyflavone-3-β-D-galactose. 5) All synthesized compounds’ structure has been comfirmed by1H NMR,13CNMR, HRMS or IR.6) All synthesized PMFs and derivatives were evaluated for their cytotoxicpotential against Hela cell lines by standard MTT method. Moreover, MTT assaysrevealed that5-hydroxylated-3,6,7,8,4′-pendamethoxyflavone11and5-hydroxylatedtangeretin13had the strongest activity, IC50values were6.788μmol/L and0.791μmol/L respectively.