A New Synthesis Method For Tanshinones

Studies have shown that tanshinones, have a broad-spectrum anti-tumor effect, suggesting that it is promising to be developed into to new anticancer drugs. However, after the analysis of the cytotoxicity of tanshinone analogues and their derivatives, we observed that:A ring of cells may replace the toxic have influence, the dione is not the key factor to inhibit tumor, and the structure-activity relationship of D-loop is still uncertain. Synthesis of tanshinone compounds is very difficult. The synthesis methods reported have many shortcomings, such as synthetic difficulty, high cost, long route and environmental pollution problems, which limit the use of tanshinone compound structure in Pharmaceutical. Therefore, an feasible chemical synthesis route for tanshinones seems necessary and important.This paper focused on the total synthesis and cytotoxicity studies of tanshinones and their derivants in order to find a lower-cost and short synthetic route for tanshinone Ⅰ and its extended objects, get more compounds with new structure, which can be used to investigate the antitumor structure-activity relationship of tanshinones, screening the target compound with expected cytotoxicity, and to support theoretical and experimental basis for the new class of tanshinone anticancer drug development.Making tanshinone Ⅰ as model compounds, we designed three kinds of tanshinones and their analogs in accordance with the existing structure-activity relationship. The first series of tanshinone compounds is obtained by transforming the A ring. The second kind of compounds is obtained by transforming the carbonyl on C ring. The third kind of compounds is obtained by transformation of the D-ring furan ring.We design two new total synthesis routes for tanshinones. The reaction process of each step is deeply explored via series of experiments. Using morpholine and propyl aldehyde as starting material, the first synthetic route obtained the important intermediates through Stork reaction and oxidation. But the intermediates are so unstable that it will affect the subsequent Diels-Alder reaction. Therefore, the feasibility of the route needs to be further investigated. In the second synthetic route, benzaldehyde and1,4-benzoquinone are selected as starting material. Then, skeleton compounds which are the third serie of compounds required for design are obtained through the witting response and the D-A reaction. Next, the second serie of compounds required for design can be obtained by the Stork reaction. This synthetic route can avoid the synthesis of unstable intermediates. Finally, the first serie of compounds required for the design are obtained through the oxidation reaction. The new synthetic route has many advantages which overcome the shortcomings of the existing synthetic route such as high cost, pollution, low yield and so on. Therefore, the route can be used in the industrial production of tanshinone I and its derivatives. As a result, the new route has synthesized a total of three series of compounds, a series of which, two have not been reported, two series of three, have not been reported,3Series4,1have not been reported.The MTT assay was adopted to examine the inhibitoty effect of Compounds1.1(Tanshinone I)、1.2(7-Methoxy-1-methyl-phenathro[2,1-b] furan-10,11-dione)、1.3(7.8-DiMethoxy-1-methyl-phenathro[2,1-b]furan-10,11-dione)on proliferation of K562cells, and the changes of cell morphology were observed by inverted phase contrast microscope. From IC50values we can conclude that the six compounds had proliferation inhibition effect on K562cells with a strength function order of Compound1.1(Tanshinone I)-1.2>>1.3.