Structure of adduct X, the last unknown of the six major DNA adducts of mitomycin C formed in EMT6 mouse mammary tumor cells.
Structure of adduct X, the last unknown of the six major DNA adducts of mitomycin C formed in EMT6 mouse mammary tumor cells.
复制标题
加合物 X 的结构，是 EMT6 小鼠乳腺肿瘤细胞中形成的丝裂霉素 C 六种主要 DNA 加合物中最后一个未知的结构。
DOI：
10.1021/tx000024j
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发表时间：
2000
影响因子：
4.1
通讯作者：
Tomasz,M
中科院分区：
文献类型：
--
作者：
Palom,Y;Belcourt,MF;Musser,SM;Sartorelli,AC;Rockwell,S;Tomasz,M
用丝裂霉素C（MC）处理EMT 6小鼠乳腺肿瘤细胞导致形成六种主要的MC−DNA加合物。我们确定了最后一个未知的（“加合物X”）是2，7-二氨基线粒体（2，7-DAM）的鸟嘌呤N2加合物，其中线粒体在其C-10位置与鸟嘌呤N2连接。指定的结构是基于直接从细胞中分离的加合物X的UV和质谱，以及其差UV、二阶导数UV和圆二色谱，从[8- 3 H]脱氧鸟苷合成，并观察其热稳定性。这些测试总共使用17 μg合成材料进行。加合物X的形成机制涉及MC还原代谢为2，7-DAM，其经历第二轮还原活化以烷基化DNA，产生加合物X和另一个2，7-DAM−鸟嘌呤加合物（加合物Y），其在鸟嘌呤N7处连接到线粒体。内收物Y在前面已经描述过。加合物X优先在GpC形成，而加合物Y优先在GpG序列形成。与MC−DNA加合物相反，2，7-DAM−DNA加合物没有细胞毒性。
Treatment of EMT6 mouse mammary tumor cells with mitomycin C (MC) results in the formation of six major MC−DNA adducts. We identified the last unknown of these (“adductX”) as a guanine N2adduct of 2,7-diaminomitosene (2,7-DAM), in which the mitosene is linked at its C-10 position to guanine N2. The assigned structure is based on UV and mass spectra of adductXisolated directly from the cells, as well as on its difference UV, second-derivative UV, and circular dichroism spectra, synthesis from [8-3H]deoxyguanosine, and observation of its heat stability. These tests were carried out using 17 μg of synthetic material altogether. The mechanism of formation of adductXinvolves reductive metabolism of MC to 2,7-DAM, which undergoes a second round of reductive activation to alkylate DNA, yielding adductXand another 2,7-DAM−guanine adduct (adductY), which is linked at guanine N7 to the mitosene. AdductYhas been described previously. AdductXis formed preferentially at GpC, while adductYfavors the GpG sequence. In contrast to MC−DNA adducts, the 2,7-DAM−DNA adducts are not cytotoxic.