ORGN 128 |
| CC-1065 and the duocarmycins belong to an extremely potent class of naturally occurring cytotoxic compounds. They have IC50 values in the picoMolar range, against the growth of cancer cells in culture. Since their discovery, numerous structure-activity relationship studies have been conducted, including seco-amino- and seco-hydroxyCBI analogs. Four analogs have entered clinical evaluation, and presently, only bizelesin remains in clinical trial. One of the severe dose limiting toxicities of all these compounds is bone marrow suppression. Consequently there is a strong interest in the design, synthesis, and testing of novel analogs that have comparable cytotoxicity, but with reduced systemic toxicity. In our laboratory, we have initiated a project to address the question of whether the chiral center present in the duocarmycins and CC-1065 is critically needed for DNA interaction and cytotoxicity. Accordingly, we have designed and synthesized several analogs of duocarmycin SA, in which the chiral center has been removed. We have also found the novel achiral amino- and hydroxy-seco-CBI analogs of the duocarmycins to exhibit potent DNA alkylating and cytotoxic properties. The results and discussion from these experiments will be presented. |
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Heterocycles, Aromatics, Materials, Devices, Switches, Combinatorial Chemistry, Metal-Mediated Reactions
8:00 PM-10:00 PM, Sunday, 13 March 2005 Convention Center -- Hall D, Poster
Division of Organic Chemistry |