Novel 1-haloalkyl-2-nitroimidazole bioreductive alkylating agents.

Solid tumors contain hypoxic cells which are relatively resistant to radiation treatment and to most forms of chemotherapy. These cells can be preferentially targeted using chemotherapeutic agents that are specifically activated by cellular reductase enzymes in the absence of oxygen. A new class of bioreductive alkylating agents based on the 2-nitroimidazole nucleus has been developed which contains a haloalkyl substituent on the N-1 position of the imidazole ring. Compounds of this series were readily reduced by mammalian NADPH-cytochrome c reductase, and reduction led to the production of an electrophilic center. This reactive component was hypothesized to be responsible for the preferential cytotoxicity of the agents of this class to hypoxic tumor cells through alkylation of cellular components.