Reductive activation of mitomycin C

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Abstract
Mitomycin C, an antitumor antibiotic, is known to require reductive activation in order to function as an alkylating agent. In this work reduction has been carried out by using radiolytically produced formate radicals that reduce mitomycin C to its semiquinone in a clean rapid one-electron reaction. The ultimate products of the reduction are cis- and trans-2,7-diamino-1-hydroxymitosene (B1 and B2) and 2,7-diaminomitosene (C). The yields of these compounds were found to be the same when the rate of reduction was varied by 11 orders of magnitude. At pH 7, one mitosene molecule is formed for every two formate radicals, while at pH 9.1, about eight mitosene molecules are formed per formate radical. The ratio of (B1 + B2)/C is < 0.4 at pH 5.7, 1.0 at pH 7, and > 3.5 at pH 9.1. Observations have been made of changes in optical absorption due to the formation of the semiquinone and hydroquinone of both mitomycin C itself and 2,7-diamino-1-hydroxymitosene (B). The direct conversion of the semiquinone form of mitomycin C into the semiquinone of B proceeds slowly, if at all. The semiquinone form of B will rapidly reduce mitomycin C (k = 7.2 .times. 108 M-1 s-1). The hydroquinone of mitomycin C undergoes changes resulting in the formation of B and C. The yields of B and C depend on pH. The kinetic data fit a scheme in which the mitomycin C hydroquinone has a pKa of 5.1, with its protonated form changing to C by a concerted rearrangement with k = 1.2 s-1, its deprotonated form changing to the hydroquinone of B with k = 0.015 s-1, and the hydroquinone of B reducing mitomycin C with k = 5 M-1 s-1. The 2,7-diamino-1-hydroxymitosenes are thus formed in a chain reaction with the formation of 2,7-diaminomitosene as a chain termination step. It is suggested that increased cell toxicity at lower pH could be due to the precursor of 2,7-diaminomitosene being an effective alkylating agent.