Studies On Synthesis And Bioactivity Of Polymethoxyfavonoids And Their Nitrogent-containing Derivatives

Flavonoids exist in most plants possessing potent antioxidant, antiviral and antitumor activity. Flavonoids show lower bioavailability, poorly soluble which limiting their use in drug development. Polymethoxyflavonoids (PMFs) refer to flavonoids that have four or more methoxy groups. PMFs have remarkable biological activity, including anti-tumor activity on HL-60 leukemia cells, breast tumor cells, mice skin cancer and other cancer cells. Meantime they also exhibit anti-inflammatory, anti-allergic, antiviral activity, antibacterial and multi-resistant reversal activity. The structural units of nitrogen-containing base are a class of important pharmacologically active groups, which can effectively improve the bioavailability and water-soluble on flavonoids. Mannich reaction and Hofmann alkylation reaction are effective methods for synthesizing nitrogen-containing natural organic-compounds, which are widely used in the synthesis of natural products and organic drug molecules. Therefore, this thesis is attempted to synthesize a series of polymethoxyflavonoids and nitrogen-containing flavonoids from quercetin, and study their biological activity against acetylcholinesterase (AChE).1.3,5,7,3',4'-Pentamethoxyflavone (1) and 5-hydroxy-3,7,3',4'- tetramethoxy flavone (2) were synthesized from low-priced quercetin via reaction of O-methylation. Under acid conditions, system of methanol or isopropanol, eight new mannich base derivatives 4-11 were performed based on Mannich reaction with Microwave heating technology using compound 2, formaldehyde and secondary amine as the materials. And aminomethylation occurred preferentially at the ortho position of the phenolic hydroxyl. The new synthetic route has the advantages of easy availability of starting materials, simple operation and good yields, so it has considerable practical value.2.5-Bromobutoxy-3,7,3',4'-tetramethoxyflavone (3) were synthesized from quercetin via reaction of O-methylation and nucleophilic substitution with two halogenated hydrocarbon. Then under solvent of acetonitrile conditions, Nine new amine derivatives 12?20 were synthesized via Hofmann alkylation reacttion using compound 3 and secondary amine as amination reagents.3. Polymethoxyflavonoids 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (22) and 3,5,6,7,8,3',4'-heptanmethoxyflavone (25) were synthesized from quercetin, through reaction of bromination,O-methylation and CuBr catalyzed Ullmann aromatic nucleophilic substitution. This route has advantages of fewer steps and good yields, which has the vital significance on the design and synthesis of quercetin derivatives.4. All the synthesized favonoids nitrogen-containing derivatives were evaluated for acetylcholinesterase (AChE) inhibitory activity by the Ellman. Test data showed that flavonoids nitrogen-containing derivatives can enhance the acetylcholinesterase (AChE) inhibitory activity, and compounds 8 (IC50=0.238 ?mol·L-1) exhibited stronger AChE inhibitory activity compared than the control drug Neoeserine methyl sulfate.5. The structure of all synthesized compounds 1-25 have been confirmed by 1H NMR,13C NMR and MS.