Targeting the mitochondrial cell death pathway with gold compounds
Targeting the mitochondrial cell death pathway with gold compounds
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DOI：
10.1016/j.ccr.2007.04.006
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发表时间：
2007-07-01
影响因子：
20.6
通讯作者：
Berners-Price, Susan J.
中科院分区：
文献类型：
--
作者：
Barnard, Peter J.;Berners-Price, Susan J.
最近有许多证据表明，线粒体在细胞凋亡（程序性细胞死亡）的调控中起着关键作用，使它们成为设计新的抗癌药物的一个有吸引力的靶点。在最近的文献中描述了针对线粒体的各种不同的癌症治疗策略。几种不同类型的金基化合物(Au（I)和Au（III）氧化态）作为潜在的抗肿瘤药物引起了人们的兴趣，有证据表明，许多化合物通过涉及线粒体细胞死亡途径的机制起作用。两种不同类型的Au(I)膦配合物显示出抗肿瘤特性，这些配合物具有线性两坐标或四面体四坐标几何形状。这两类似乎都针对线粒体，但可能涉及不同的机制，这与它们与生物配体进行配体交换反应的不同倾向有关。抗关节炎的金(I)膦药物，金氧蛋白，已被证明通过选择性抑制硫氧还蛋白还原酶的线粒体异构体来诱导细胞凋亡，硫氧还蛋白还原酶已成为潜在的新药物靶点。金(I)化合物是已知硫氧还蛋白还原酶最有效的抑制剂之一，可归因于金(I)与氧化还原活性硒半胱氨酸残基的结合。另一方面，[Au(dppe)(2)]（+）和相关的四面体Au(I)膦配合物不像二坐标线性Au(I)配合物那样容易发生配体交换反应。它们的抗肿瘤活性可能源于亲脂性、阳离子性质，就像在线粒体中积累的其他离域亲脂性阳离子一样。
There is much recent evidence showing that mitochondria play a critical role in the regulation of apoptosis (programmed cell death), making them an attractive target for the design of new anticancer drugs. A variety of different strategies targeting mitochondria for cancer therapy have been described in recent literature. Several different classes of gold-based compounds (in both Au(I) and Au(III) oxidation states) have attracted interest as potential antitumour agents and there is evidence that many act by mechanisms involving mitochondrial cell death pathways. Two distinct classes of Au(I) phosphine complexes display antitumour properties, these having either linear two-coordinate, or tetrahedral four-coordinate geometries. Both classes appear to target mitochondria, but different mechanisms are likely to be involved, related to their differing propensity to undergo ligand exchange reactions with biological ligands. The anti-arthritic Au(I) phosphine drug, auranofin, has been shown to induce apoptosis via selective inhibition of the mitochondrial isoform of thioredoxin reductase, an enzyme which has emerged as a potential new drug target. Gold(I) compounds are among the most potent known inhibitors of thioredoxin reductase, attributable to binding of Au(I) to the redox-active selenocysteine residue. On the other hand [Au(dppe)(2)](+), and related tetrahedral Au(I) phosphine complexes, do not undergo ligand exchange reactions as readily as two-coordinate linear Au(I) complexes. Their antitumour activity may stem from the lipophilic, cationic properties, as for other delocalised lipophilic cations that accumulate in mitochondria.