Studies On The Synthesis Of Bioactive Apigenin And Acacetin Glycosides And Flavonoids Glycoconjugates

Flavonoid glycosides are widely distributed in the plant kingdom, and aregenerally found in vegetables, fruits as secondary metabolites. They exhibit a broadspectrum of biological activities including antitumor, antimicrobial,anti-inflammatory, anti-clotting and antidiabetic properties as well as protections ofthe role of the cardiovascular system and liver tissue. The natural product naringin, amember of the flavanone group, can be isolated in large amount from the rinds ofsome citrus species, and has been reported to have broad pharmacological activity.Research has shown that the biological activity of flavonoids is connected to thetype and conformation of sugar on the A ring, therefore, to synthesize bioactiveflavonoids from the readily available and cheap naringin has the advantages of lowcost, short synthetic steps, simple operation and good yields. In order to meet theneeds for selecting substances with biological activities and developing new drugs,the thesis aims at the studies on the semisynthesis of apigenin and acacetin7-O-β-D-glycosides as well as the usage of the click chemistry to synthesis of a newtype of glycoconjugate from naringin.1、The natural flavone acacetin12which is an important ingredient of cosmetics,was synthesized from naringin, through dehydrogenation, methylation,h-ydrolyzation. The synthesis of4′-O-benzyl apigenin11is accomplished based o-nthe dehydrogenation, benzyl protection of phenol hydroxyl, hydrolyzation ofnaringin.2、Firstly, the glycosyl donor peracetylglycosyl bromide reacted with flavone aglycon11and12followed by deprotection afforded a series of flavone-7-O-glycosides1-10. Peracetylglucose bromide, peracetylgalactose bromide areselected to be glycosyl donor. The glycosylation reaction was carried out using CHCl₃/H₂O biphase conditions with TBAB as phase-transfer catalyst in thecondition of anhydrous potassium carbonate. The glycosylation reaction methodhas a relatively high yield and stereoselectivity. Among all the synthesized flavoniods, apigenin-7-O-β-D-glucoside3, apigenin-7-O-β-D-galactoside6,acacetin-7-O-β-D-glucoside8, acacetin-7-O-β-D-galactoside10are the natural products.3、The flavone acacetin11and12was connected to the sugar moiety by usingthe method of click chemistry to offer a series of flavonoids sugar conjugates for thefirst time. The method has the advance of high yield and stereoselectivity. In the synthesis process, the ether acetylene bond cleavage can be effectively blocked by a"step-feeding" process during the preparation, to simplify the post-processingsteps to improve the reaction yield.4、The inhibitory effect on different caner cell lines of the synthesized compounds was evaluated by using the method of MTT. Their cytotoxic potential against five human cancer cell lines: myeloid leukemia （HL-60）, liver carcinoma （SMMC-7721）, lung carcinoma （A-549）, breast carcinoma （MCF-7） and intestinal carcinoma （SW480） was evaluated, According to the bioactive research, the compound4′-O-benzyl apigenin research, the compound4′-O-benzyl-apigenin-7-O-β-D-acetylglucoside1, the compound acacetin-7-O-β-D-acetylglucoside5and the compound apigenin-7-O-β-D-acetylgalactoside7have significantantitumor activity in vitro.5、In the paper,20flavonoid glycosides have been semi-synthesized, Among the synthesized target compounds, the10flavonoid glycoconjugates were all new compounds, the natural product8was the first synthesized and the synthesis of natural products apigenin-7-O-β-D-glucoside3, apigenin-7-O-β-D-galactoside6and acacetin-7-O-β-D-galactoside10were efficiently improved by the new synthetic routs. The structures of the synthesized compounds have been confirmed by¹H NMR, MS and IR.