Synthesis And Anticancer Activity Research Of1,3-diarylbutylene Neolignan

Neolignan is a kind of natural products with extensive physiological activity. They possess the basic skeleton of phenylpropanoid dimmers. Currently the neolignan mainly comes from the extraction of natural products, which often expends a lot of manpower and material resources. Moreover, the excessive utilization of natural resources can also lead to the ecological balance problem. Therefore, the synthesis of these compounds by chemical methods is gradually becoming the hot spot in the research fields of organic chemistry and pharmaceutical chemistry.In this thesis, the1,3-diarylbutylene compounds in study had the basic skeleton of neolignan. In recent years, synthesis work carried on this kind of compounds have been reported, which mainly focused on aromatic olefins dimerization catalyzed by expensive transition metal such as Pd, Ni, Co, Ru, etc. However, such procedures often required of rigorous condition, high cost, even resulted in environmental pollution, which were far away from the requirements of industrial production. Based on the above reasons, we are dedicated to seeking a more simple and economic environment route for the sythesis of1,3-diarylbutylene neolignan.The research work in present thesis includes the following three aspects:(1) Based on the Mn(II)/Co(II)/PhP(O)HOR/O2redox system raised by Professor Ishii, and the research achievements made on organic phosphorus chemistry in our laboratory, a new synthetic methods involving phosphite ester for1,3-diarylbutylene compounds was accidentally discovered. The optimum molar ratio of a-asarone to O-butyl-phenyl ester in the catalytic system was confirmed to be1:3. Model reaction conditions including a-asarone as substrate, acetic acid as solvent, and reaction temprature at90℃for24h under O2flow were established, with the yield of products from a-asarone self-coupling reaching76%. Furthermore, a catalytic system that was effective for self-coupling of electron-rich aryl olefin a-asarone—the Mn(Ⅱ)/Co(Ⅱ)/PhP(O)HOR/O2redox system—was put forward.(2) In order to study the validity of the system and indentify the reaction mechanism,10aryl olefins derivatives with different substituted groups were designed and synthesized. Seven1.3-diarylbutylene neolignan compounds40a～40g with45%to76%yield were obtained employing these ten compounds as substrates under the catalytic system mentioned above.It was found that self-coupling reaction of electron-rich aryl olefin can occurs effectively in such system, while that of substrates with electron withdrawing groups such as the nitrostyrene can not proceed. Based on the research of literatures and experimental data, a mechanism of free radical oxidative coupling reaction was proposed. And the radical annihilation experiments were designed to validate the mechanism. Finally, the free radicals reaction mechanism in the present reaction process was preliminarily determined.(3) The inhibitory activity in vitro of the seven as-synthesized1,3-diarylbutylene compounds towards human breast cancer cells (MCF-7), human hepatoma cells (Bel-7402), human lung cancer cells (A549) and human cervical carcinoma cell (Hela) was investigated using the MTT assay methods. Results showed that certain inhibitory effect on the four cancer cells was observed over compounds40a-40g. While obvious inhibitory effect on human hepatoma cells was obtined with the compounds of40b, with the IC50value18.9μg/ml.