The Studies On The Synthesis And Antitumor Activity Of 3,6,8-Monosubstituted Quercetin Derivatives

Quercetin,which belongs to the flavonol family, is one of the most widespread flavonoids natural products. Quercetin has been found in the leaves, stems, lowers, fruits of different plants in the form of glycosides. In the recent years, a lot of studies show that quercetin possess variety of biological activities including the effect of expansion of coronary vessels, lowering blood lipids, anti-inflammatory, antioxidant, antitumor, anti-diabetic complications and other physiological effects. All that have inspired more and more scientists’research attention this type of molecules. In the past years, the research of this area is mainly focused on the preparation and bioactivity study of the hydroxyl derivative of quercetin, and the studies on it’s 3,6,8-monosubstituted carbon-carbon coupling derivatives is rarely reported.We would like to report the design and synthesis of 3,6,8-monosubstituted quercetin derivatives in this thesis. Rutin was used as the starting material which was converted into quercetin in acidic condition. The selective protection of the 5-hydroxy groups of the quercetin really helped the next step highly regio-selective 6 and 8 monohalogenation. After the Suzuki coupling reaction or Heck coupling reaction, the 4-6 steps synthetic approach was accomplished and 27 novel 6,8-monosubstituted quercetin derivatives were obtained in 6%-34% overall yield.3-carbon-carbon coupling substituted quercetin derivatives were prepared by first protection the four hydroxyl groups of rutin which was followed by hydrolysis the sugar group from the 3-hydroxy position. After the 3-hydroxy was activated Suzuki-Coupling or Heck-Coupling reaction. Provided 14 novel 3-substituted quercetin derivatives in 5%-31% overall yield. The structures and purities of the prepared key intermediates and target compounds (41) were confirmed by 1H-NMR, 13C-NMR and MS, among them 40 compounds have not been reported before. The influence of the reaction conditions of the key Suzuki and Heck coupling such as temperature, solvents, and alkali catalyst types were also examined and the efficient synthetic routes of the 3 series targets were optimized.Finally, the results of the antitumor activity evaluation against leukemia cells K562, liver cancer HepG2 and colon cancer HT-29 indicated that the 3,6 and 8 monosubstituted quercetin derivatives possessed better antitumor activity than their mother molecule quercetin, among them 8 monosubstituted derivatives showed the best inhibition. The target molecules 1-5、1-7 and 1-8 inhibited the HepG2 tumor cell with the IC50 value of 0.38μM, 0.83μM and 0.75μM, respectively.