Controlling the rates of reductively-activated elimination from the (indol-3-yl)methyl position of indolequinones
Controlling the rates of reductively-activated elimination from the (indol-3-yl)methyl position of indolequinones
复制标题
DOI：
10.1039/b009652k
复制
发表时间：
2001-01-01
期刊：
影响因子：
--
通讯作者：
Moody, CJ
中科院分区：
文献类型：
--
作者：
Everett, SA;Naylor, MA;Moody, CJ
合成了一系列取代的3-(4-硝基苯氧基)甲基吲哚-4,7-二酮(Q)。研究了吲哚核心上的取代模式对 4-硝基苯酚消除速率的影响，作为酚醚连接体断裂后药物释放的模型。还原成自由基阴离子（Q(.-)）或氢醌（QH(2)）后，4-硝基苯酚从（吲哚-3-基）甲基位置消除。 Q(.-)自由基在[O-2]处的半衰期大约为5 mu mol dm(-3)，典型的肿瘤缺氧，t(1/2)大约为0.3-1.8 ms，较高的值与较高的还原电位相关。在相同的氧浓度下，QH(2)的自氧化半衰期明显更长(t(1/2)约8-102分钟)，并且在4μmol dm(-3)超氧化物歧化酶存在下仍然更长(t(1/2)约8-19小时)。尽管吲哚醌能够高效消除4-硝基苯酚，但只有3-羰基取代衍生物的Q(.-)自由基能够以足够短的半衰期（t(1/2)约41-2 ms）来消除4-硝基苯酚，以与电子转移到氧竞争，因此有可能将离去基团靶向缺氧组织。即使在正常组织中预期的氧气浓度下，氢醌对氧的敏感性也不足以阻止 4-硝基苯酚的消除（t(1/2) 约为 1.5-3.5 秒）。通过在吲哚基羰基位置引入富电子取代基，可以控制还原断裂的速率。这可能被证明是设计基于吲哚醌的生物还原药物递送系统的重要因素。
A series of substituted 3-(4-nitrophenyloxy)methylindole-4,7-diones (Q) were synthesised. The effects of substitution patterns on the indole core on rates of elimination of 4-nitrophenol as a model for drug release following fragmentation of a phenolic ether linker were studied. After reduction to either the radical anion (Q(.-)) or hydroquinone (QH(2)) elimination of 4-nitrophenol occurred from the (indol-3-yl)methyl position. The half-lives of Q(.-) radicals at [O-2]approximate to5 mu mol dm(-3), typical of tumour hypoxia, were t(1/2)approximate to0.3-1.8 ms, the higher values associated with higher reduction potentials. Half-lives for the autoxidation of the QH(2) were markedly longer at the same oxygen concentration (t(1/2)approximate to8-102 min) and longer still in the presence of 4 mu mol dm(-3) superoxide dismutase (t(1/2)approximate to8-19 h). Although the indolequinones were able to eliminate 4-nitrophenol with high efficiency only Q(.-) radicals of the 3-carbinyl substituted derivatives did so with sufficiently short half-lives (t(1/2)approximate to 41-2 ms) to compete with electron transfer to oxygen and therefore have the potential to target the leaving group to hypoxic tissue. The hydroquinones are not sufficiently oxygen sensitive to prevent the elimination of 4-nitrophenol (t(1/2)approximate to1.5-3.5 s) even at oxygen concentrations expected in normal tissue. By incorporating electron rich substituents at the indolyl carbinyl position it is possible to control the rate of reductive fragmentation. This may prove an important factor in the design of an indolequinone-based bioreductive drug delivery system.