Design, Synthesis and Cytotoxic Activities of Anthraquinones and Chalcones

• Main Authors: Chi-Huang Teng, 鄧志煌
• Other Authors: 林忠男
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/67392882610079555670

博士 === 高雄醫學大學 === 藥學研究所博士班 === 94 === Natural anthraquinones and chalcones exhibited various biological activities. Some anthraquinones mediated their cytotoxicity through apoptosis. In previous reports, a series of anthraquinones were evaluated for their cytotoxicity. In order to understand the structure and cytotoxicity relationship, we continued to design and synthesize twenty one anthraquinone derivatives. In a previous study, we found that chalcone, 2'',5''-dimethoxy-4-hydroxychalcone (29) had significantly cytotoxic activity, therefore we had also to design and synthesize a series of chalcones, all of the compounds of anthraquinone and chalcone were evaluated for their cytotoxic activity and DNA strand scission activity. Anthraquinones were also evaluated for inhibitory effect on the platelet aggregation induced by epinephrine in human PRP. We also predicted their anti-cycloxygenase activity by molecular docking. Compound 3-[3-(4-Methylpiperazinopropoxy)]-9,10-anthraquinone (14) showed significantly cytotoxic activity against HT-29 and MCF-7. MCF-7 were treated with various concentrations of 14 for different time periods. The appearance of cells with low DNA stainability formed a “sub-G1 peak” and DNA fragmentation in MCF-7 cells was significantly observed after 72 hrs. These compounds might induce cell death by apoptosis. Among chalcone derivatives, the chalcones which have thio moiety, 2'',5''-Dimethoxy-2-thienylchalcone (32), 2'',5''-Dimethoxy-3-thienylchalcone (33) and 2'',5''-Dimethoxy-2-(5-methylthienyl)chalcone (35) had potent cytotoxic activity against MCF-7. Compound 35 showed significantly cytotoxic activity against colorectal cancer cell line. A “sub-G1 peak” increased and nuclear fragmentation in MCF-7 cells was significantly observed after 72 hrs. We suggested that these compounds might also induce cell death by apoptosis. 1-Hydroxy-3-[3-(diethylamino)-2-hydroxypropoxy]-9,10-anthraqunione (44) mediated DNA breakage in the presence of Cu (II) (300, 200, 100 ?嵱). The convertion of supercoiled DNA to the relaxed form was inhibited with neocuproine, a Cu (I)-specific sequestering agent. The result suggested that Cu (I) was the essential intermediate in the 44 mediated DNA cleavage reaction. Compound 44 in the presence of Cu (II) induced DNA degradation was completely inhibited by the addition of KI and catalase while superoxide dismutase (SOD) did not protect the DNA from strand breakage. We suggested that compound 44 induce H2O2 and OH• generation in the presence of Cu (II) and subsequent damage to cellular DNA. In epinephrine induced platelet aggregation of human PRP, compounds 9, 17, 42 and 43 prevented secondary aggregations and suppressed the primary aggregation at high concentrations induced by epinephrine. We supposed that these compounds might partially inhibit the thromboxane synthesis. In the molecular docking, compounds with the high Ligscore2 and the Jain score more than 2.46, revealed anti-cyclooxygenase activity. The synthetic chalcones 30-38 had high Ligscore2 and their Jain score also more than 2.46. It suggested that they might reveal anti-cyclooxyganase activity. In epinephrine induced platelet aggregation of human PRP, compounds 32, 33 and 35 prevented secondary aggregations. We suggested that these compounds might partially inhibit the thromboxane synthesis.