STUDIES ON NOVEL NQO1-DIRECTED QUINOLINEQUINONE ANTITUMOR AGENTS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 NAD(P)H：苯醌氧化还原酶(NQO1)是一类被称为生物还原抗癌药的重要酶。NQO1在实体瘤中高表达，有报道表明NQO1活性的抗肿瘤醌类化合物可能对表达NQO1的肿瘤细胞具有选择性毒性。我们最近发现，作为NQO1良好底物的拉旺霉素类似物，与没有NQO1的同基因细胞相比，对NQO1水平升高的癌细胞株具有选择性毒性。这一发现促使我们重新检查底物效率和抗肿瘤活性所需的最低结构元素 目的是生产更简单的化合物，具有最佳的性能，如溶解性和膜透过性。开发了一种生产新型喹诺酮类药物的合成方法，并描述了一项包括有效性和安全性评估的生物测试计划。使用重组人NQO1的分光光度和高效液相色谱分析将用于测量苯二酚的还原速率。含有和不含有NQO1的人BE结肠癌细胞株将用于测试NQO1依赖的毒性，原代人血管内皮细胞和骨髓单个核细胞将用于评估安全性潜力。该项目的总体目标是生产具有潜在临床用途的抗肿瘤药物的专利药物。

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.