The Synthesis And Bioactivity Identification Of Isoflavone And Steroid Derivatives

Seeking highly effective anti-cancer drugs with low toxicity has been the focus of enormous amount of research efforts in tumor therapy. In the fields of chemical medicine exploitation, Isoflavone and steroids derivatives are potential candidates for the treatment of cancer and for many other diseases, such as cardiovascular diseases and osteoporosis. In recent years, large amount of data have demonstrated that Genistein has broad-spectrum anti-tumor and anti-proliferation bioactivities. Although many mechanisms have been proposed, the exact one has yet to be identified. In addition to its anti-tumor activity, previous study in our institute found that Genistein may also alleviate hemotopoietic injury induced by irradiation. It has been found that the metabolic product of estrogen-2-methosyestradiol- represses angiogenesis in tumor, thereby inhibiting the growth of tumor. What attracts our attention is that some delicate changes in chemical structure may result in widely different bioactivity in isoflavone and steroid derivatives, which suggests we may modify the structure of these compounds so as to obtain effective anti-tumor compounds with low toxicity.In this study, we modified several isoflavone and steroid derivatives, and evaluated their bioactivities through in vivo and in vitro experiments. The aim of our study is to find novel compounds with high and broad-spectrum anti-tumor activity and low toxicity, as well as to lend experimental clues for the potential clinical use of these compounds. Herein, the following experiments were designed and performed:1. Synthesizing a series of target compounds by introducing different alkalescence groups into 2- and 7-position hydroxyl of isoflavones (Glycitein Genistein and 7,8,4'-trihydroisoflavone) ,and by introducing different alkalescence side chain into 3-position of estrone.2. Evaluating the selective inhibition of cell proliferation of 24 isoflavone derivatives and 4 steroids by observing these compounds'influence on the survival rate of 5 differentcell lines(tumor cell lines: MCF Hela SMMC-7721 SGC-7901 and normal cell line IEC-6) by MTT, thus screening out the compounds with high anti-tumor activities and investigating their possible mechanisms.3. Establishing the heterologous graft models of human breast cancer in nude mice(MCF-7),evaluating the anti-tumor activities of the screened compounds in vivo and their influence on the morphology of organs in treated mice.Results:1. Obtained 12 isoflavone derivatives and 2 steroid derivatives, which were to be together with previously synthesized 14 compounds to form the compound library, which was to be screened in subsequent study.2. In vitro experiments demonstrated the 28 compounds differ in their effects on proliferation of tested cell lines. Most of the compounds have marked inhibition effects on the proliferation of tumor cell lines. F11 and ZE2 have the most distinct inhibition on proliferation, and induce direct death of cell lines. Furthermore, F12 markedly promotes proliferation of several cell lines tested.3. In vivo experiments in nude mice revealed that compounds F11 and ZE2 have prominent inhibitory effects on the growth of heterologous graft of human breast cancer as compared with saline treated controls. Under our regimen of drug administration, no observable adverse effects were found in mice organs in those treated by F11 and ZE2. Therefore, F11 and ZE2 were the appropriate target compounds that we screened out, which needed to be further investigated as to its functioning mechanism or their possible application to clinical uses.4. Thus far, no protection of patent rights is found for F11 and ZE2.