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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA089566-14
Application #
8680010
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fu, Yali
Project Start
2000-12-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Purdue University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Beck, Daniel E; Lv, Wei; Abdelmalak, Monica et al. (2016) Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons. Bioorg Med Chem 24:1469-79
Beck, Daniel E; Abdelmalak, Monica; Lv, Wei et al. (2015) Discovery of potent indenoisoquinoline topoisomerase I poisons lacking the 3-nitro toxicophore. J Med Chem 58:3997-4015
Nguyen, Trung Xuan; Abdelmalak, Monica; Marchand, Christophe et al. (2015) Synthesis and biological evaluation of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines as potential dual topoisomerase I (Top1)-tyrosyl-DNA phosphodiesterase I (TDP1) inhibitors. J Med Chem 58:3188-208
Beck, Daniel E; Agama, Keli; Marchand, Christophe et al. (2014) Synthesis and biological evaluation of new carbohydrate-substituted indenoisoquinoline topoisomerase I inhibitors and improved syntheses of the experimental anticancer agents indotecan (LMP400) and indimitecan (LMP776). J Med Chem 57:1495-512
Kiselev, Evgeny; Sooryakumar, Dhriti; Agama, Keli et al. (2014) Optimization of the lactam side chain of 7-azaindenoisoquinoline topoisomerase I inhibitors and mechanism of action studies in cancer cells. J Med Chem 57:1289-98
Lv, Peng-Cheng; Agama, Keli; Marchand, Christophe et al. (2014) Design, synthesis, and biological evaluation of O-2-modified indenoisoquinolines as dual topoisomerase I-tyrosyl-DNA phosphodiesterase I inhibitors. J Med Chem 57:4324-36
Conda-Sheridan, Martin; Reddy, P V Narasimha; Morrell, Andrew et al. (2013) Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase I (Tdp1) and topoisomerase I (Top1). J Med Chem 56:182-200
Conda-Sheridan, Martin; Park, Eun-Jung; Beck, Daniel E et al. (2013) Design, synthesis, and biological evaluation of indenoisoquinoline rexinoids with chemopreventive potential. J Med Chem 56:2581-605
Coletta, Andrea; Castelli, Silvia; Chillemi, Giovanni et al. (2013) Solvent dependency of the UV-Vis spectrum of indenoisoquinolines: role of keto-oxygens as polarity interaction probes. PLoS One 8:e73881
Balana-Fouce, Rafael; Prada, Christopher F; Requena, Jose Maria et al. (2012) Indotecan (LMP400) and AM13-55: two novel indenoisoquinolines show potential for treating visceral leishmaniasis. Antimicrob Agents Chemother 56:5264-70

Showing the most recent 10 out of 54 publications