Champeil Elise, Cheng Shu-Yuan, Huang Bik Tzu, Conchero-Guisan Marta, Martinez Thibaut, Paz Manuel M, Sapse Anne-Marie
John Jay College of Criminal Justice, New York, 524 West 59th Street, New York, NY 10019, USA; The Graduate Center of the City University of New York, New York, NY 10016, USA.
John Jay College of Criminal Justice, New York, 524 West 59th Street, New York, NY 10019, USA.
Bioorg Chem. 2016 Apr;65:90-9. doi: 10.1016/j.bioorg.2016.02.003. Epub 2016 Feb 11.
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.
丝裂霉素C（MC）和去氨甲酰丝裂霉素C（DMC，MC在C10位缺少氨基甲酸酯的衍生物）是DNA烷基化剂。它们的细胞毒性归因于其产生DNA单加合物以及链内和链间交联（ICL）的能力。MC和DMC在肿瘤细胞中产生的主要单加合物在鸟嘌呤-丝裂霉素键的碳1处具有相反的立体化学结构：MC为反式（或α），DMC为顺式（或β）。我们假设反式或顺式加合物引起的DNA结构局部破坏是MC和DMC产生不同生化反应的原因。获得带有顺式和反式MC/DMC损伤的DNA底物对于验证这一假设至关重要。带有反式损伤的合成寡核苷酸可通过仿生方法获得。然而，这种方法不会产生顺式加合物。本报告介绍了顺式丝裂霉素DNA加合物的首次化学合成。我们还通过分析脱氧鸟苷与MC或DMC在各种活化条件下反应中顺式和反式加合物的形成，研究了这两种药物在单核苷酸水平上表现出的立体选择性。此外，我们进行了密度泛函理论计算以评估这些反应的能量。在自催化或双功能条件下的直接烷基化优先产生MC和DMC的α加合物。DFT计算表明，在双功能活化下，热力学上有利的加合物对于MC是α、反式，对于DMC是β、顺式。这表明双链DNA结构可能稳定/定向活化的前药，从而在细胞环境中，对于DMC来说，有可能形成热力学上有利的β产物。
