Hypoxic cells which are found in solid tumors are resistant to anticancer drugs and radiation therapy. Thus, for effective anticancer chemotherapy, it is important to identify drugs with selective toxicity towards hypoxic cells. Quinoxaline 1,4-dioxides (QdNOs) are heterocyclic aromatic N-oxides that have been found to possess potent antibacterial activities (inhibit microbial DNA synthesis) especially under anaerobic conditions; thus they are under evaluation as bioreductive drugs for the treatment of solid tumors (1). We investigated the ability of four differently substituted QdNOs to inhibit cell growth and induce cell cycle changes in two human tumorigenic epithelial cell lines under oxic conditions. We also evaluated the toxicity of these drugs to cancer cells cultured under hypoxic conditions. Two epithelial cell lines (the T-84 human colon cancer-derived cell line, and the SP-1 keratinocyte cell line) were treated with various doses of the QdNOs and harvested at different times after treatment. Proliferation and cell cycle results showed a structure-function relationship in the activity of the various QdNO compounds with the 2-benzoyl-3-phenyl-6,7-dichloro-derivative of QdNO (DCBPQ) being the most potent cytotoxin and hypoxia-selective drug. The 2-benzoyl-3-phenyl (BPQ) and the 2-acyl-3-methyl-derivative of QdNO (AMQ) were less cytotoxic but arrested almost 50% of the cells in the G2M phase of the cell cycle at doses of 30 and 120 μM, respectively. The tetramethylene derivative of QdNO (TMQ) did not affect the growth and cycling of cells cultured in air and was the least potent cytotoxin to hypoxic cells. Our results indicate that the QdNOs are hypoxia-cytotoxic drugs whose activity varies according to the substituents on the quinoxaline 1,4-dioxide heterocycle. Because of their selective toxicity to hypoxic cells (cells found in human tumors), these drugs may provide useful therapeutic agents against solid tumors.

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