Synthesis of Mitomycin C and Decarbamoylmitomycin C N(2) deoxyguanosine-adducts

• Published in: Bioorganic chemistry Vol. 65; pp. 90 - 99
• Main Authors: Champeil, Elise, Cheng, Shu-Yuan, Huang, Bik Tzu, Conchero-Guisan, Marta, Martinez, Thibaut, Paz, Manuel M, Sapse, Anne-Marie
• Format: Journal Article
• Language: English
• Published: United States 01.04.2016
• Subjects: Deoxyguanosine - chemical synthesis; Deoxyguanosine - chemistry; DNA Adducts - chemical synthesis; DNA Adducts - chemistry; Mitomycin - chemical synthesis; Mitomycin - chemistry; Mitomycins - chemical synthesis; Mitomycins - chemistry; Molecular Conformation; Quantum Theory; Stereo preference; Post-oligomerization; Deoxyguanosine; Mitomycin C
• ISSN: 1090-2120
• DOI: 10.1016/j.bioorg.2016.02.003

Mitomycin C (MC) and Decarbamoylmitomycin C (DMC) - a derivative of MC lacking the carbamate on C10 - are DNA alkylating agents. Their cytotoxicity is attributed to their ability to generate DNA monoadducts as well as intrastrand and interstrand cross-links (ICLs). The major monoadducts generated by MC and DMC in tumor cells have opposite stereochemistry at carbon one of the guanine-mitosene bond: trans (or alpha) for MC and cis (or beta) for DMC. We hypothesize that local disruptions of DNA structure from trans or cis adducts are responsible for the different biochemical responses produced by MC and DMC. Access to DNA substrates bearing cis and trans MC/DMC lesions is essential to verify this hypothesis. Synthetic oligonucleotides bearing trans lesions can be obtained by bio-mimetic methods. However, this approach does not yield cis adducts. This report presents the first chemical synthesis of a cis mitosene DNA adduct. We also examined the stereopreference exhibited by the two drugs at the mononucleotide level by analyzing the formation of cis and trans adducts in the reaction of deoxyguanosine with MC or DMC using a variety of activation conditions. In addition, we performed Density Functional Theory calculations to evaluate the energies of these reactions. Direct alkylation under autocatalytic or bifunctional conditions yielded preferentially alpha adducts with both MC and DMC. DFT calculations showed that under bifunctional activation, the thermodynamically favored adducts are alpha, trans, for MC and beta, cis, for DMC. This suggests that the duplex DNA structure may stabilize/oriente the activated pro-drugs so that, with DMC, formation of the thermodynamically favored beta products are possible in a cellular environment.