The long-term goals of this project are to design, synthesize and evaluate novel topoisomerase I (Top1) inhibitors for the treatment of cancer. The clinical studies will allow future problems revealed by the clinical results to be addressed immediately and effectively. This could include structural modification to address potential problems resulting from drug toxicity, resistance, unfavorable pharmacokinetics, and lack of potency. The Top1 design strategy will involve an evaluation of the fundamental forces stabilizing the inhibitor/enzyme/DNA ternary complexes through medicinal chemistry, computer graphics molecular modeling, molecular mechanics, ab initio quantum mechanics, and biochemical studies. In addition, the design of new Top1 inhibitors will be aided by crystallography inhibitor/enzyme/DNA of ternary complexes, which will facilitate structure-based drug design. A variety of synthetic methods will be employed in the syntheses of new Top I inhibitors, including indenoisoquinoline-camptothecin hybrids termed "aromathecins", nitrogen analogues of the aromathecins, and azaindenoisoquinolines. The resulting anticancer agents will be targeted to cancer cells and solid tumors through attachment of low molecular weight homing ligands that will be removed metabolically after selective uptake into cancer cells as opposed to normal cells. The conjugates will be evaluated by testing the release mechanism, monitoring inhibition of cell proliferation, blocking the attachment of the homing ligand to cancer cells to help elucidate mechanism of action, and determining selectivities in the NCI panel of cancer cell cultures. The phosphodiester bond linking Tyr723 of Top I to the 3'-phosphate of DNA in stalled cleavage complexes is hydrolyzed by tyrosyl-DNA-phosphodiesterase I (Tdp1). Since Tdp1 inhibitors counteract the action of Top1 inhibitors, Tdp1 inhibitors might interact synergistically with Top1 inhibitors. A goal of this project is to incorporate both Top1 and Tdp1 inhibitory activities into the same anticancer agents, which are expected be significantly more potent than those of Top I inhibitors lacking Tdp1 inhibitory activity. This will exploit a unique discovery of Tdp1 inhibitory activity in several indenoisoquinolines. The Top1 inhibitors resulting from this study will be evaluated in a variety of assays including those involving: 1) Top1-mediated DNA cleavage reactions;2) Top1-DNA linkage and reversibility of cleavage complexes;3) kinetics of cleavage complex formation and reversal;4) DNA unwinding to monitor intercalation;5) inhibition of Top1-mediated DNA relaxation;6) protein-linked strand breaks induced by inhibitors in mammalian cells;7) cytotoxicity assays in cancer cell cultures, including camptothecin-resistant cells lines;8) hollow fiber studies and xenograft testing;9) antibiotic activity vs. African trypanosomes.
This is a competitive renewal application for the design and synthesis of topoisomerase I inhibitors for the treatment of cancer in humans. The project has already generated two clinical candidates, indimitecan and indotecan, which will undergo clinical evaluation at the National Cancer Institute. The continuation of the project will allow the medicinal chemistry, crystallography, and biochemistry components of the project to remain actively involved so that the potential limitations of the two clinical candidates can be addressed effectively.
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