DNA cross-linking by intermediates in the mitomycin activation cascade

Journal Article · Tue Jun 27 00:00:00 EDT 1989 · Biochemistry; (USA)

DOI:https://doi.org/10.1021/bi00439a049· OSTI ID:5030636

Cera, C; Egbertson, M; Teng, S P; Crothers, D M; Danishefsky, S J ^[1]

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1. Yale Univ., New Haven, CT (USA)

The authors have assayed the cross-linking of oligonucleotides containing repeated mitomycin-reactive CpG sites in order to assess the factors that enhance activation of the carbamoyl function at C{sub 10}, yielding efficient mitomycin cross-linking. Drugs studied include mitomycin C (MC), N-methylmitomycin A (NMA), and the aziridinomitosene of NMA (MS). Drugs were reduced both by catalytic hydrogenation and by dithionite. They find that cross-linking by fully reduced NMA can be increased severalfold by addition of either excess dithionite reductant or the oxidant FeCl{sub 3}. Enhancement by FeCl{sub 3} is not seen with MC or MS, but excess dithionite increases cross-linking by all three compounds. They explain the action of Fe{sup 3+} by postulating production of the semiquinone of the monoadduct of mitomycin reacted at the C{sub 1}-position; according to this mechanism, departure of the carbamate from C{sub 10} is more efficient for the semiquinone than for the hydroquinone. However, the results imply that the hydroquinone can also function as a cross-linking agent. Excess dithionite beyond that required for stoichiometric reduction, activates the carbamate 2-3-fold for cross-linking. They find that the fully reduced leucoaziridinomitosene is highly unstable in solution, yet it produces efficient cross-linking. Hence, this compound is highly reactive in DNA alkylation and a good candidate for the role of primary alkylating agent.

• OSTI ID: 5030636
• Journal Information: Biochemistry; (USA), Vol. 28:13; ISSN 0006-2960
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
DNA
ALKYLATION
MITOMYCIN
CROSS-LINKING
OLIGONUCLEOTIDES
ATP
DOSE-RESPONSE RELATIONSHIPS
ELECTROPHORESIS
IRON CHLORIDES
PH VALUE
PHOSPHORUS 32
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTIMITOTIC DRUGS
ANTINEOPLASTIC DRUGS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
CHEMICAL REACTIONS
CHLORIDES
CHLORINE COMPOUNDS
DAYS LIVING RADIOISOTOPES
DRUGS
HALIDES
HALOGEN COMPOUNDS
IRON COMPOUNDS
ISOTOPES
LIGHT NUCLEI
NUCLEI
NUCLEIC ACIDS
NUCLEOTIDES
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
PHOSPHORUS ISOTOPES
POLYMERIZATION
RADIOISOTOPES
TRANSITION ELEMENT COMPOUNDS
550201* - Biochemistry- Tracer Techniques