The Role of C6 and C7 in DNA-Protein Crosslink Formation in Aziridinomitosene Treatments
Don L. Warner
Mitomycin C, a naturally-occurring anticancer agent, functions by hindering cell replication and growth via the alkylation of DNA. However, mitomycin C must be reduced to a leucoaziridinomitosene structure to be active, and the reduction step is believed to cause many negative side effects in those treated with this compound. Aziridinomitosenes are synthetic compounds that mimic the activated mitomycin C structurally and functionally, but some analogs do not require reduction for activation. In addition to alkylating DNA, aziridinomitosenes may form crosslinks between DNA and proteins, a method of cytotoxicity that has not been previously observed. This event is significant because cells are less capable of repairing DNA/protein crosslinks than those between DNA strands. Previously synthesized aziridinomitosenes have already been shown to have higher DNA interstrand crosslink yields and increased potency than mitomicin C. Aziridinomitosenes have four electrophilic sites where alkylation can occur: C1, C6, C7 and C10. Our hypothesis is that C6 and C7 are, in part, responsible for DNA/protein adduct formation. To test this hypothesis, aziridinomitosenes with methyl substitutions at C6, at C7 and at both C6 and C7 are being synthesized with the goal to show the significant differences in potency that are presumed to be caused by changing the active site. The synthesis, which entails approximately 20 individual steps, has progressed to pre-cyclization compounds for all three analogs. Once subjected to the oxazolium salt/azomethine ylide cycloaddition reaction, they will be completed after six additional reactions. If our hypothesis is correct, the analogs with only C6 or C7 blocked (and not both) should continue to produce DNA/protein crosslinks, whereas the analog with methyl groups at both C6 and C7 should not. Work specific to the synthesis of these compounds as well as related studies will be presented.