Maliepaard M, de Mol N J, Janssen L H, Hoogvliet J C, van der Neut W, Verboom W, Reinhoudt D N
Department of Pharmaceutical Chemistry, Utrecht University, The Netherlands.
J Med Chem. 1993 Jul 23;36(15):2091-7. doi: 10.1021/jm00067a006.
The reductive activation of mitosene compounds was studied with cyclic voltammetry and HPLC analysis. Reduction of mitosenes, possessing good leaving groups at C-1 and C-10, was shown to result in loss of these groups at pH 7.0 and pH 6.0. The loss of leaving groups from mitosenes occurred faster at lower pH. Mitosenes without good leaving groups were found to be stable upon reduction. In the presence of acetoxy groups at C-1 and C-10, the C-10 site is the most reactive site upon reductive activation. This is opposite to the case of mitomycin C, where the C-1 site is the first to react upon reduction. At pH 6.0 without reduction, acid degradation also caused the loss of leaving groups of mitosenes, although at a very slow rate. In contrast to reductive activation, upon acid degradation of a diacetoxymitosene the C-1 group appeared to be lost faster. Electrochemical as well as dithionite reduction of a bifunctional (diacetoxy) mitosene compound in the presence of calf thymus DNA at pH 5.5 resulted in the formation of DNA interstrand cross-links. Depending on activation method, this diacetoxymitosene was at least as efficient in DNA cross-linking as mitomycin C under comparable conditions.
采用循环伏安法和高效液相色谱分析法研究了米托烯化合物的还原活化。研究表明，在C-1和C-10位具有良好离去基团的米托烯在pH 7.0和pH 6.0条件下还原会导致这些基团的丢失。在较低pH值下，米托烯离去基团的丢失速度更快。发现没有良好离去基团的米托烯在还原时是稳定的。在C-1和C-10位存在乙酰氧基时，C-10位是还原活化时最具反应活性的位点。这与丝裂霉素C的情况相反，丝裂霉素C在还原时C-1位首先发生反应。在pH 6.0且未还原的情况下，酸降解也会导致米托烯离去基团的丢失，尽管速度非常缓慢。与还原活化相反，二乙酰氧基米托烯酸降解时C-1基团似乎丢失得更快。在pH 5.5条件下，双功能（二乙酰氧基）米托烯化合物在小牛胸腺DNA存在下进行电化学还原以及连二亚硫酸盐还原，会导致DNA链间交联的形成。根据活化方法的不同，在可比条件下，这种二乙酰氧基米托烯在DNA交联方面至少与丝裂霉素C一样有效。
