Our goal is to develop new mitomycin analogs which are equally potent (dose level) to mitomycin C, but have a superior antitumor effect and cause less leukopenia (the limiting clinical toxicity). These analogs are designed to be consistent with the mitomycin mode of action and structure-activity relationships. New 7-substituted analogs of mitomycin C will be prepared, but emphasis will be on optimizing antitumor activity around three structural types: alkyl thiols and related disulfides, amino acids, and potential chelating agents. Their structures will incorporate features such as secondary and aryl amines that were found to confer high activity in previous analogs. Promising initial studies on metal chelation by mitomycins will be expanded. The structures of chelates will be elucidated with the aid of 13C NMR and UV absorption studies. Polarographic reduction potentials of the chelates will be measured and attempts will be made to correlate them with antitumor activity. The effect of chelation on the production of superoxide and hydroxyl radicals upon reduction and reoxidation of mitomycin analogs will be studied. Among the new potential chelating agents to be synthesized will be series of compounds in which the number and nature of ligands and the ring sizes are varied. An EDTA derivative of mitomycin C, capable of chelating iron, will be prepared. A new type of mitomycin analog will be synthesized and tested. It will combine the structural features of our 1-substituted mitosenes and Anderson's bis(hydroxymethyl)-1H-phyrrolizine biscarbamates. This combination should confer the advantage of bioreductive activation on the good activity of the pyrrolizine biscarbametes. The existing arrangements on antitumor screening and leukopenia determination by Bristol Laboratories and NCI contractors will be maintained.
