Catalytic organometallic anticancer complexes
Catalytic organometallic anticancer complexes
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DOI：
10.1073/pnas.0800076105
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发表时间：
2008-08-19
影响因子：
11.1
通讯作者：
Sadler, Peter J.
中科院分区：
文献类型：
--
作者：
Dougan, Sarah J.;Habtemariam, Abraha;Sadler, Peter J.
有机物复合物提供了纯有机分子无法获得的化学性质，因此可能是药物作用的新机制。我们发现碘代配体和σ-给体/π-受体苯基偶氮吡啶配体的存在赋予了半夹心“piano-stool”钌芳烃配合物[（eta（6）-arene）Ru（azpy）I]（+）（其中arene =对伞花烃或联苯，azpy = N，N-二甲基苯基-或羟基苯基-偶氮吡啶）在水溶液中对配体取代的显著惰性。令人惊讶的是，尽管这种惰性，这些复合物对人卵巢A2780和人肺癌A549细胞具有高度细胞毒性。在A549细胞中的细胞毒性捕获实验表明，细胞毒性来自活性氧的增加。通过电化学测量证实了这些偶氮吡啶Ru-II配合物的氧化还原活性。第一个单电子还原步骤（半波电位-0.2至-0.4 V）可归因于配体的偶氮基团的还原。相反，未结合的偶氮吡啶配体不容易被还原。令人感兴趣的是，钌络合物在与三肽谷胱甘肽（γ-L-Glu-L-Cys-Gly）的反应中充当催化剂，三肽谷胱甘肽是以毫摩尔浓度存在于细胞中的强还原剂;在微摩尔钌浓度存在下，毫摩尔量的谷胱甘肽被氧化成谷胱甘肽二硫化物。一个氧化还原循环涉及谷胱甘肽攻击的偶氮键的协调偶氮吡啶提出。这种基于配体的氧化还原反应为催化药物的设计提供了新的概念。
Organometallic complexes offer chemistry that is not accessible to purely organic molecules and, hence, potentially new mechanisms of drug action. We show here that the presence of both an iodido ligand and a sigma-donor/pi-acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich "piano-stool" ruthenium arene complexes [(eta(6)-arene)Ru(azpy)I](+) (where arene = p-cymene or biphenyl, and azpy = N,N-dimethylphenyl- or hydroxyphenyl-azopyridine) in aqueous solution. Surprisingly, despite this inertness, these complexes are highly cytotoxic to human ovarian A2780 and human lung A549 cancer cells. Fluorescence-trapping experiments in A549 cells suggest that the cytotoxicity arises from an increase in reactive oxygen species. Redox activity of these azopyridine Ru-II complexes was confirmed by electrochemical measurements. The first one-electron reduction step (half-wave potential -0.2 to -0.4 V) is assignable to reduction of the azo group of the ligand. In contrast, the unbound azopyridine ligands are not readily reduced. intriguingly the ruthenium complex acted as a catalyst in reactions with the tripeptide glutathione (gamma-L-Glu-L-Cys-Gly), a strong reducing agent present in cells at millimolar concentrations; millimolar amounts of glutathione were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations. A redox cycle involving glutathione attack on the azo bond of coordinated azopyridine is proposed. Such ligand-based redox reactions provide new concepts for the design of catalytic drugs.