Hepatocellular carcinoma (HCC) develops through cirrhosis brought on by chronic liver injury. This chronic injury results in fibrogenesis that damages the normal liver circulatory system and leads to a shortage of blood perfusion and oxygen delivery. Moreover, in tumor tissues, a high rate of cell proliferation in the tumor cells and abnormalities of structure and function of tumor vessels increases the need for oxygen. We are interested in developing therapies that target hypoxic HCC cells and have been experimenting with nitroimadazoles conjugated to the methylated nordihydroguaiaretic acid (NDGA) anticancer agents developed in our lab.

In hypoxic tumor cells, nitroimidazoles undergo a series of enzymic reductions, mediated by nitroreductase enzymes, and followed by ring fragmentation. Reactive radicals are thus generated, which then irreversibly bind to the cellular components. After the compounds enter the cell, reduction enables more drugs to accumulate in the cell by a favorable concentration gradient. In normoxic cells, the presence of oxygen prevents the enzymic reduction of nitroimidazole, and hence no binding occurs. In addition, nitroimidazole derivatives show preferential toxicity to hypoxic cells as hypoxic cytotoxins. Their cytotoxicity toward hypoxic cells is a result of abstraction of hydrogen from target molecules by free radicals formed in the reduction of the nitro group.