Studies On The Synthesis And Properties Of Flavonols And Coumarins As Well As Their Glycosides And Glycoconjugates

Flavonol and coumarin compounds are two kinds of widely spread natural medicinal products. They are precursors of the lead compounds, which possess a variety of biological activities including anti-tumor, anti-HIV virus, and enzyme inhibitors treatment. In natural products, the activities of active ingredients are related to the existence of sugars. During the process of glycosylation, the conformation of the molecule was modified to improve its solubility and orientation, and finally increase its affinity and capacity to biological receptor. To obtain good biological activity and orientation compounds, herein we developed a strategy of click chemistry to synthesize flavonoids and coumarins glucoconjugates, and then investigated the biological activity of these compounds.1. Three natural flavonols kaemferol (8a),3-hydroxyl-5,7,4’-trimethoxyl flavone (10b) and rhamnocitrin (8c); three new novel aurones4,6,4’-trihydroxyl dihydroaurone (4a),4,4’-dihydroxyl-6-methoxyl dihydroaurone (4c), and4-hydroxyl-6,4’-dimethoxyl dihydroaurone (4d) were semi synthesized using naringin as staring materials by the reaction steps including glycoside hydrolysis, dehydrogenation, benzyl protection, O-methylation, DMDO oxidation or Algar-Flynn-Oyamade (AFO) reaction and debenzylation. The synthetic methods of DMDO oxidation for flavones to flavonols and AFO reaction for chalcones to aurones were efficient improved in the key steps. These methods have the advantages of simple operation and good yields.2. Based on the method of "Click chemistry",24new flavonol glycoconjugates (12b,13a,13c,14a-c,15b,16a,16c,17a-c,18b,19a,19c,20a-c,21b,22a,22c and23a-c) were synthesized from flavonols (10a-c) and sugars (Glucose, Galactose, Lactose and Maltose). Intermolecular Cu (I) catalyzed1,3-dipolar cycloaddition of the alkynes of flavonols and corresponding glycosyl azides is the key step. During the process, the manipulation of step-by-step feeding can block the ether-acetylene bond cleavage, simplify the processing steps, and increased the yields of the reaction to80%above.3. All synthesized flavonol glycoconjugates(12b,13a,13c,14a-c,15b,16a,16c,17a-c,18b,19a,19c,20a-c,21b,22a,22c and23a-c) were evaluated for their potential cytotoxicity against leukemia cell lines (HL-60), hepatocellular carcinoma cell lines (SMMC-7721), lung cancer cell lines (A-549), breast cancer cell lines (MCF-7), and colon cancer cell lines (SW480) by the standard3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) method in vitro. The results showed that compounds13a and22c showed potent cytotoxicity against SMMC-7721, compounds13a and16c showed moderate cytotoxicity against MCF-7, compound13c showed cytotoxicity against MCF-7, compounds15b and22c showed potent cytotoxicity against MCF-7; compounds13a,15b and16c showed cytotoxicity against HL-60, compound16c showed cytotoxicity against A-549, compound22c showed potent cytotoxicity against A-549. Cytotoxicity of all the compounds mentioned above are similar or even improved compared with the positive control, cisplatin (DPP).4. Four3-carboxylic acid coumarin compounds (25a-d) and two3-acetyl coumarin compounds (26b and26c) were synthesized through the Knoevenagel reaction; two7-hydroxyl coumarin compounds (31and32) were synthesized through Pechmann reaction respectively. The starting materials we needed are easy obtained, including aldehyde, resorcinol, diethyl malonate, or ethyl acetoacetate. In the catalysis of TFA, two new fluorescent dipyrroles (27b and27c) were obtained. And then, optimized the reaction conditions of condensation between3-acetyl coumarins and pyrroles. With two7-hydroxyl coumarins, isopentenyl bromide and farnesyl bromide as raw materials, two7-O-isopentenyl coumarin (28a and28b), and two7-O-farnesyl coumarin (29a and29b) were synthesized in the ways of7-O-eher bond using the improving phase transfer catalysis approach. Among them, compounds28a,28b and29b are not reported in any literature.5. With two7-hydroxyl coumarins, carbohydrates (glucose, galactose, lactose and maltose) as staring materials,16novel7-O-coumarin glycosides (33a-d,36a-d) were obtained by using the improving phase transfer catalysis approach. With7-hydroxyl coumarin (31and32) and carbohydrates (Glucose, Galactose, Lactose and Maltose) as start materials, the method of "Click chemistry" to firstly used to synthesize a new type of8coumarin glycoconjugates (38a-39d) under the catalysis of fresh Cu (I) through the key step of azide-alkyne1,3-dipolar cycloaddition. Then, the spectral properties of7-O-coumarin glycosides and glycoconjugates (32,34a-d,36a-d,38a-d,39a,39b and39d) were studied by using fluorescence spectra. It’s obvious to show that the polarity of the solvents influence the fluorescence intensity dramatically. Coumarins (36a-d,39a,39b and39d) with sugar modification existed fluorescence quench and its glycosides possessed the strongest ability to fluorescence quench. Unlike the compound32, the maximum emission wavelength of coumarins compounds modified by sugars structural doesn’t change in water.