ALKYLATION REACTIONS OF MITOMYCIN-C AT ACID PH

Mitomycin C readily alkylates inorganic phosphate and the phosphate group of various nucleotides in aqueous solution at acid pH. The products of this type of reaction are 2,7-diaminomitosenes containing a phosphate group in the 1-position. The reaction is appreciable only below pH 5, requiring protonation of the aziridine ring of mitomycin C (pKa’ = 4). The specific reactions studied were the following: alkylation of inorganic phosphate yields 1,2-cis-and trans-2,7-diaminomitosene 1-phosphate, in greater than 9/1 ratio. Alkylation of 5′-uridylic acid results in cis-and trans-2,7-diaminomitosene 1-(5′-uridy-late), in approximately 4/1 ratio. 5′-Uridine triphosphate is alkylated at its terminal phosphate group, to give the corresponding 1-substituted 2,7-diaminomitosene, also with predominant cis composition. The structure of these products was proven by quantitative phosphate analysis, ultraviolet spectra, and enzymatic degradation into known products. UpU yields a small amount of a mitosene adduct which was not characterized. Uridine itself is not alkylated by mitomycin C. Hydrolytic ring opening of the protonated aziridine ring of mitomycin C competes with the phosphate alkylation reactions, yielding cis-and trans-2,7-diamino-1-hydroxymitosenes. The phosphate compounds described represent the first characterized examples of alkylation of nucleotides by mitomycin C, supporting the previous hypothesis that the mitomycins are biological alkylating agents. © 1979, American Chemical Society. All rights reserved.