Mitomycin C and Decarbamoyl mitomycin C

Mitomycin C and Decarbamoyl mitomycin C DNA adducts

Figure 1: MC and DMC major DNA-adducts.

The mitomycins are a family of antitumor antibiotics made by Streptomyces. One member of this family, mitomycin C (MC), is currently used to treat certain cancers. Its cytotoxic and antitumor activity is attributed to its ability to alkylate DNA monofunctionally and bifunctionally, resulting in DNA monoadducts as well as interstrand and intrastrand cross-links (ICL). 10-Decarbamoylmitomycin C (DMC) is a derivative of MC lacking the carbamate groups on C-10. As such, DMC was originally thought to only alkylate DNA monofunctionally. However, when EMT6 mouse mammary tumor cells were treated with DMC, both ICL and DNA monoadducts were produced. The major adducts generated by MC and DMC have different stereochemistry at carbon 1: trans (or alpha, a) for MC and cis (or beta, b) for DMC. In addition, biochemical responses to the two drugs are strikingly different.
The MC and DMC adducts present an opportunity for investigating the individual structure–activity relationships of multiple DNA adducts. In this case, it will enable direct comparisons of biological effects induced by a different stereochemistry at carbon1 (Fig. 1).
Our immediate goal is to synthesize the adducts 1b and 2b depicted in figure 1. So far, we have reported the synthesis of two amino precursors for the production of adducts 1a and 1b. In addition, we have also described the synthesis of monoadduct 1a. The alternative approach to adduct 1a which we developed opens doors to the synthesis of adducts with beta stereochemistry. This is all the more essential as the biomimetic method developed for the production of these adducts is inefficient for the production of adducts with beta stereochemistry.

Figure 2: Triaminomitosene precursor for the adduct 1a (trans).

Figure 3: Triaminomitosene precursor for the adduct 1b (cis).

Figure 4: Synthesis of adduct 1a (trans).