MEDI 60 |
| The cytotoxic mechanisms of coplanar annelated polycyclic compounds such as doxorubicin and ellipticine are caused by intercalation in human DNA and modification of topoisomerase II. Tetracyclic ring structure compounds, such as benzo-naphthofurandiones and furoquinolinediones were synthesized by base-catalyzed condensation of dichloro-naphthoquinones and quinolinediones with phenolic derivatives, respectively. Their dialkylaminoalkoxy derivatives were prepared by reactions of the produced hydroxybenzofurandiones with dialkylaminoalkyl chlorides. The cytotoxicity of the synthesized compounds was evaluated against various human cancer cell lines and the topoisomerase II inhibition of them was assessed by a decatenation assay. The cytotoxicity of all the compounds synthesized was much higher than that of ellipticine. Benzofuroquinolinediones exhibited more potent inhibitory activity than naphthofurandiones, which indicate that the introduction of nitrogen in the ring is considerably important for the cytotoxicity. Most of the compounds exhibited excellent topoisomerase II inhibitory activity which was 11~100% at a concentration of 5 mM. The IC50 values of selected compounds showed were 0.39~1.19 mM which is about 65~200 times more potent than that of etoposide (IC50 = 78.4 mM). |
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General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster
Division of Medicinal Chemistry |