MEDI 282 |
| The indenoisoquinolines are a class of cytotoxic topoisomerase I inhibitors with inherently greater molecular stability than the clinically used camptothecin derivatives irinotecan and topotecan. Previous results from our laboratory have indicated that the biological activity of the indenoisoquinolines is significantly enhanced by nitration of the isoquinoline ring. Furthermore, a synergism was found to exist between the nitrated isoquinoline ring and a methylenedioxy-substituted indenone ring. In order to investigate this synergism, nitrated analogues were synthesized with the indenone ring substituted with methoxy groups. The results of this study lead to the conclusion that the previously observed synergism is not related to an increase in the number of electron-donating substituents on the indenone ring, with a single methoxy group at the 9- position affording superior biological activity. Furthermore, this study indicates that sterics cause a deleterious effect for substituents intercalating between the nonscissile DNA strand. A hypothetical binding model has been developed in order to rationalize these results and concludes that π-stacking, visualized by electrostatic complementarity with DNA base pairs, is important for the intercalation and biological activity of the indenoisoquinoline analogues.
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Medicinal Chemistry Award Symposium
9:00 AM-12:10 PM, Tuesday, 12 September 2006 Moscone Center -- Room 102, Oral
Division of Medicinal Chemistry |
