Iminium ion chemistry of mitosene DNA alkylating agents. Enriched 13C NMR and isolation studies.
Described herein is a study of the reductive alkylation chemistry of mitosene antitumor agents. We employed a 13C-enriched electrophilic center to probe the fate of the iminium ion resulting from reductive activation. The 13C-labeled center permitted the identification of complex products resulting from alkylation reactions. In the case of DNA reductive alkylation, the type and number of alkylation sites were readily assessed by 13C NMR. Although there has been much excellent work done in the area of mitosene chemistry and biochemistry, the present study provides a number of new findings: (1) The major fate of the iminium ion is head-to-tail polymerization, even in dilute solutions. (2) Dithionite reductive activation results in the formation of mitosene sulfite esters as well as the previously observed sulfonate adducts. (3) The mitosene iminium ion alkylates the adenosine 6-amino group as well as the guanosine 2-amino group. The identification of the latter adduct was greatly facilitated by the 13C-label at the electrophilic center. (4) The mitosene iminium ion alkylates DNA at both nitrogen and oxygen centers without any apparent base selectivity. The complexity of mitosene reductive alkylation of DNA will require continued adduct isolation studies.
Ouyang
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Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
Skibo
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EB
D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification; D002021:Buffers; D002247:Carbon Isotopes; D018736:DNA Adducts / Q000737:chemistry*; D003839:Deoxyadenosines / Q000737:chemistry; D003849:Deoxyguanosine / Q000737:chemistry; D004227:Dithionite / Q000737:chemistry; D007097:Imines / Q000737:chemistry*; D008937:Mitomycins / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D019163:Reducing Agents / Q000737:chemistry
C100960:1,10-bisacetoxymitosene WV15; D018906:Antineoplastic Agents, Alkylating; D002021:Buffers; D002247:Carbon Isotopes; D018736:DNA Adducts; D003839:Deoxyadenosines; D007097:Imines; D008937:Mitomycins; D019163:Reducing Agents; D004227:Dithionite; C046001:mitosene; D003849:Deoxyguanosine