Development of the anti-cancer promoting activity prediction method for the quinones which assume oxidation-reduction potential as a key parameter

氧化还原电位作为分析参数进行了评价的基础上，提出了一般性的抑制作用之间的相关性EB病毒早期抗原（EBV-EA）的激活和氧化还原电位的醌。基于该结果，可以通过测量醌衍生物的还原电位来可靠地评价醌衍生物的抗肿瘤活性，而无需体外筛选。合成了11个多羟基蒽醌类化合物和8个O-甲基大黄素衍生物，并从决明子中分离得到了奥布妥辛等天然蒽醌类化合物，整理了基础数据。此外，我们还建立了一种简便、快速的高效液相色谱法分离测定大黄中大黄素等蒽醌类化合物的方法。我们研究了这些化合物对EBV-EA活化的抑制作用与氧化还原电位之间的相关性。结果发现，在生理pH下的第一还原电位与羟基和/或甲氧基多取代蒽醌对EBV-EA活化的抑制作用相关，可以作为预测抗肿瘤促进作用的有用参数。由于1-氮杂蒽醌与蒽醌具有相同的相关性，我们合成了环上含有氧、氮和/或硫原子的杂醌，并使用循环伏安法检测这些杂醌的氧化还原电位。然后，我们研究了电位与癌细胞生长的抑制作用或醌类化合物的致死作用之间的相关性，因此我们发现活性效应与第一还原电位之间存在良好的相关性。LC/APCI-MS结果表明大黄素在Raji细胞中的代谢产物为8-O-甲基大黄素和羟基大黄素。

The oxidation-reduction potential as a parameter for analysis was evaluated on the basis of suggesting a generality to the correlation between the inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation and oxidation-reduction potentials for quinones. Based on this result, a reliable evaluation of the anti-tumor activity of quinone derivatives can be made by measuring their reduction potentials, without in vitro screening. 11 Polyhydroxyanthraquinones and 8 O-methylemodin derivatives were synthesized and natural anthraquinones, such as obutusin, were isolated from cassia seed to organize the fundamental data. In addition, we have developed a simple and rapid high-performance liquid chromatography method to separate and determine anthraquinones, such as emodin, in rhubarb. We examined the correlations between the inhibitory effects on EBV-EA activation and oxidation-reduction potentials about these obtained compounds. As a result, it was found that the first reduction potential at a physiological pH correlated with the inhibitory effects of hydroxy and/or methoxy polysubstituted anthraquinones on EBV-EA activation and could be a useful parameter as a prediction method of the anti-tumor promoting effects.As 1-azaanthraquinone had the same correlation as anthraquinones, we synthesized heteroquinones including oxygen, nitrogen and/or sulfur atoms in the rings, and examined the oxidation-reduction potential of these heteroquinones using cyclic voltammetry. Then, we investigated the correlations between the potentials and inhibitory effects of cancer cell growth or lethal effect of heteroquinones, so that we found good correlations about the effects of activity and the first reduction potentials. Thus, the first reduction potential seems to be promising parameter for predicting the biological activity as anthraquinones.Furthermore, it was clarified that the metabolites of emodin in Raji cells were 8-O-methylemodin and orhydroxy-emodin by LC/APCI-MS.