Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin C

Mitomycin C (MC), an antitumor drug, and decarbamoylmitomycin C (DMC), a derivative of MC, alkylate DNA and form deoxyguanosine monoadducts and interstrand crosslinks (ICLs). Interestingly, in mammalian culture cells, MC forms primarily deoxyguanosine adducts with a 1“‐R stereochemistry at the guanine–mitosene bond (1”‐α) whereas DMC forms mainly adducts with a 1“‐S stereochemistry (1”‐β). The molecular basis for the stereochemical configuration exhibited by DMC has been investigated using biomimetic synthesis. Here, we present the results of our studies on the monoalkylation of DNA by DMC. We show that the formation of 1“‐β‐deoxyguanosine adducts requires bifunctional reductive activation of DMC, and that monofunctional activation only produces 1”‐α‐adducts. The stereochemistry of the deoxyguanosine adducts formed is also dependent on the regioselectivity of DNA alkylation and on the overall DNA CG content. Additionally, we found that temperature plays a determinant role in the regioselectivity of duplex DNA alkylation by mitomycins: At 0 °C, both deoxyadenosine (dA) and deoxyguanosine (dG) alkylation occur whereas at 37 °C, mitomycins alkylate dG preferentially. The new reaction protocols developed in our laboratory to investigate DMC‐DNA alkylation raise the possibility that oligonucleotides containing DMC 1“‐β‐deoxyguanosine adducts at a specific site may be synthesized by a biomimetic approach. Decarbamoylmitomycin C (DMC) forms DNA deoxyguanosine monoadducts both at GpC and CpG sequences. The major deoxyguanosine adducts produced have the opposite stereochemical configuration at each sequence in mammalian DNA. The GpC sequence is the major target for mammalian DNA (42 % CG) in culture cells by this drug and the major adduct has 1“‐β (cis) stereochemistry at C1”. In CG rich DNA, formation of 1“‐α (trans) adduct is favored.