| Flavonoids are an important class of natural products, which are widely found in nature. It was proved that flavonoids had a variety of biological activities, such as antioxidant, antibacterial, anti-tumor, anti-viral, and anti-inflammatory activity.We synthesized two different series of flavonoid derivatives according to appropriate structural modifications on apigenin, kaempferol and quercetin, which were distributed widely. Then the in vitro bioactivities and structure-activity relationship were systematically evaluated to bacteria, plant pathogenic fungi, DPPH radical scavenging and cancer cell lines. The objective of this research was to search and find flavonoid compounds with higher bioactivities, simple structures and easy to synthesize. To provide for the new drug development candidate lead compounds and build theoretical foundation to subsequent structural optimation and medicinal development. According to our present results, the conclusions were made as follows.1. Twenty-six C-7and C-8aminomethyl flavonoid derivatives were synthesized. Five C-8aminomethyl flavonoid derivatives and five flavonoid derivatives containing amine group on C-7were abtained by structural modification. The structural characterizations were determined by NMR,and ESI-MS. In vitro antibacterial and antiproliferative assay indicated compounds abtained by structural modification had higher activities than synthetic flavonoid compounds. Based on the experiment results and the molecular structure of the natural flavonoids, we determined the structural modification on C-7and C-8positions of apigenin, kaempferol, and quercetin.2. Apigenin reacted with dihaloalkane, then with aliphatic amines. So, twenty apigenin7-O derivatives were gained. Meantime, five kaempferol7-O derivatives and five quercetin7-O derivatives were abtained according to different synthetic route. The chemical structures of these compounds were characterized using NMR, and ESI-MS. In vitro antibacterial activity against two Gram-positive bacteria(Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coliand Pseudomonas aeruginosa) of them was evaluated by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) method. The result showed that the activity of compounds with alicyclic chain substituent was higher than aliphatic chain substituent. Apigenin derivatives exhibited relatively better inhibition of Gram-positive bacteria than Gram-negative bacteria. And they all showed higher antibacterial activities than the parent apigenin. The MIC values of compounds with alicyclic chain substituent (18g-18j and19g-19j) were1.95-7.8μg/mL, and the MBC values of them were3.91-15.61μg/mL. However, the derivatives of kaempferol and quercetin displayed relatively higher antibacterial activities in vitro against Gram-negative strains than Gram-positive strains. Compounds21a and23a with aromatic amines having electron-withdrawing groups on its phenyl ring showed the strongest inhibitory activity, better than tetracycline and close to ampicillin. In vitro antifungal activity of these compounds was evaluated with the growth rate method against Botrytis cinerea Pers., Fusarium graminearum, Fusarium oxysporum f. sp. vasinfectum, Fusarium bulbigenum, Colletot Tichum Gloeosporioid.es, Alternaria solani, and Fusarium solani. The result showed that the activity of them was better than the parent compounds at the concentration of100μg/mL. Compound19i exhibited relatively higher activity in apigenin derivatives, and compounds21c and23c had the best inhibitory activity. The inhibitory ratios of23c against Colletot Tichum Gloeosporioides and Alternaria solani were higher than hymexazol. In vitro antiproliferative activity of compounds was detected on human cervical (HeLa), human hepatocellular liver (HepG2), human lung (A549), and human breast (MCF-7) cancer cells using MTT method. The activity of compounds with alicyclic chain substituent was better, compound19j showed the best activity in apigenin derivatives, and23c containing electron-withdrawing groups in its structure had the highest activity in kaempferol derivatives and quercetin derivatives.3. Ten apigenin derivatives, fifteen kaempferol derivatives and fifteen quercetin derivatives containing aminomethyl groups on the C-8position were synthesized by Mannich reaction. The structures were elucidated by NMR, and ESI-MS. In vitro antibacterial activity indicated compounds with alicyclic chain substituent was better, and had relatively better inhibition of Gram-positive bacteria than Gram-negative bacteria. The MIC and MBC values of compound26o were1.95μg/mL and3.91μg/mL against Gram-positive bacteria, comparable with the positive control tetracycline. In vitro antifungal activity displayed quercetin derivatives were higher than apigenin derivatives and kaempferol derivatives, and most of compounds with alicyclic chain substituent were better. The antioxidant activity was determined using the DPPH radical scavenging assay. Compound26n showed the strongest activity with IC50of93.8μg/mL. The antiproliferative activities of the compounds were analyzed against four human cancer cell lines. Most of compounds with alicyclic chain substituent had the better activity. Compound26k displayed the strongest activity against HeLa and HepG2cells with the IC50of8μg/mLand6μg/mL, which were higher than the positive control5-FU. Compound26o had the strongest activity against A549and MCF-7 cells, comparable with5-FU.In conclusion, this study in developing antibacterial agent and looking for a safe and efficient anti-cancer lead compounds are important. In7-O modified derivatives, kaempferol derivatives and quercetin derivatives had stronger bioactivities than its parent compounds. Compounds with alicyclic chain substituent in C-8modified derivatives showed the strongest activities. They can be developed as antimicrobial agent, antioxidant agent and anti-cancer drugs in the further study. |
PDF Full Text Request