(a) Mitomycin is a clinically used antitumor antibiotic that acts by disrupting DNA synthesis through covalent bondforming reactions with deoxyguanosine in DNA. Maria Tomasz (Hunter College) and others have shown that alkylation of DNA by mitomycin occurs by a complex series of mechanistic steps.

The process begins with reduction of the quinone ring in mitomycin to its hydroquinone form, followed by elimination of methanol from the adjacent ring to form an intermediate called leuco-aziridinomitosene. One of the paths by which leuco-aziridinomitosene alkylates DNA involves protonation and opening of the three-membered aziridine ring, resulting in an intermediate cation that is resonance stabilized by the hydroquinone group. Attack on the cation by N2 of a deoxyguanosine residue leads to a monoalkylated DNA product, as shown in the scheme. Write a detailed mechanism to show how the ring opening might occur, including resonance forms for the cation intermediate, followed by nucleophilic attack by DNA. (Intra- or interstrand cross-linking of DNA can further occur by reaction of another deoxyguanosine residue to displace the carbamoyl group of the initial mitosene-DNA monoadduct. A cross-linked adduct is also shown.)
(b) 1-Dihydromitosene A is sometimes formed from the cation intermediate in part (a) by loss of a proton and tautomerization. Propose a detailed mechanism for the formation of 1-dihydromitosene A from the resonance-stabilized cation of part (a).

OCONH2 OH OCONH (a) Writea CH O OCH CH2O ring opening. Resonance-stabilized cation intermediate CH NH CH NH Mitomycin A Leuco-aziridinomitosene alkylation by N2 of a (b) Write a mechanism for OH -OCONH, HN DNA CH2O -Deoxyribose CH DNA A monoadduct of mitomycin with DNA NH2 OCONH2 CH,O second alkylation by N2 of another in DNA CHa NH2 DNA 1-Dihydromitosene A DNA NH HN DNA CH30 -Deoxyribose CH DNA NH2 A cross-linked adduct of DNA with mitomycin