STUDIES ON NOVEL NQO1-DIRECTED QUINOLINEQUINONE ANTITUMOR AGENTS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. NAD(P)H:quinone oxidoreductase (NQO1) is an important enzyme for activation of a class of antitumor agents known as bioreductive antitumor quinones. NQO1 is highly expressed in solid tumors, and reports suggest that antitumor quinones that are bioactivated NQO1 may be selectively toxic to NQO1-expressing tumor cells. We have recently discovered that analogues of lavendamycin, a complex, natural quinone from Streptomyces lavendulae, that are good substrates for NQO1 are selectively toxic to cancer cell lines with elevated NQO1 levels compared to isogenic cells without NQO1. This finding prompted us to reexamine the minimum structural elements necessary for both substrate efficiency and antitumor activity with the objective of producing simpler compounds with optimal properties such as solubility and membrane permeability. A synthetic approach for production of novel quinolinequinones has been developed, and a plan for biological testing that includes both efficacy and safety assessment is described. Spectrophotometric and HPLC assays using recombinant human NQO1 will be used to measure rates of quinone reduction. Human BE colon carcinoma cell lines with and without NQO1 will be used to test NQO1-dependent toxicity, and primary human endothelial and bone marrow mononuclear cells will be used to assess safety potential. The overall goal of this project is to produce patentable agents with potential as clinically useful antitumor drugs.