NOVEL A RING AND E RING MODIFIED CAMPTOTHECIN ANALOGS

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Topoisomerase I (topo I) inhibitors are among the most promising new anti-neoplastic agents available. In 1996, two campothecin (CPT) analogs received regulatory approval for use in patients with solid malignancies: topotecan for previous treated patients with advanced ovarian cancer, and CPT-11 (Irinotecan) for patients with advanced colorectal carcinoma. To date, topo I inhibitors have not been effective against certain forms of cancer, despite the biochemical evidence that suggests topo I is good target in these tumor types. What is needed is a "third generation" of topo I inhibitors, that succeed the activity of 2nd generation agents CPT-11 and TPT just as these agents succeeded CPT. We propose to develop and evaluate novel topo I inhibitors that have dual activity as both (i) potent, reversible topo I inhibitors, and (ii) topo I-mediated DNA alkylating agents. We have the following specific aims: 1. To characterize 7-alkyl-10,11-methylenedioxycompatothecin analogs with respect to their ability to produce stable cleavable complex with DNA and topoisomerase I. These include the 20(S)-glycinate esters for water solubility and stability of the lactone ring. 2. To develop 7-substituted-10,11-methylenedioxycamptothecin analogs that bind covalently to topoisomerase I-DNA complexes by a topoisomerase I-mediated mechanism. 3. To develop camptothecin analogs that have stabilized lactone rings, thereby preventing pH-dependent ring opening and deactivation of the drugs. 4. To evaluate the new camptothecin analogs against in vitro and in vivo cancer cells, with particular emphasis in tumor types such as prostate cancer that respond poorly clinically to currently available camptothecin analogs.