Screening organometallic binuclear thiosemicarbazone ruthenium complexes as potential anti-tumour agents: cytotoxic activity and human serum albumin binding mechanism
Screening organometallic binuclear thiosemicarbazone ruthenium complexes as potential anti-tumour agents: cytotoxic activity and human serum albumin binding mechanism
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DOI：
10.1039/c3dt00028a
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发表时间：
2013-01-01
影响因子：
4
通讯作者：
Tomaz, Ana Isabel
中科院分区：
文献类型：
--
作者：
Demoro, Bruno;de Almeida, Rodrigo F. M.;Tomaz, Ana Isabel
本文报道了四种含5-硝基呋喃基药效团的缩氨基硫脲（TSC）与{Ru（p-cym）}（p-cym =对伞花烃）配合物的体外抗肿瘤活性。所述化合物是通式[Ru-2（p-cym）（2）（L）（2）]-X-2的二聚体结构，其中X = Cl-、PF 6-和L =去质子化的5-硝基糠醛TSC（L1），以及N-甲基（L2）、N-乙基（L3）和N-苯基（L4）衍生物。在体外筛选前体[RuCl 2（p-cym）]（2）、所有TSC配体L1-L4及其相应的复合物1-4对一系列人癌细胞系（HL-60急性早幼粒细胞白血病、A2780卵巢腺癌、MCF 7乳腺癌和PC 3 IV级前列腺癌）的细胞毒性。虽然前体络合物被发现是无活性的，并且L4仅在MCF 7细胞系中表现出中等活性，但L4与{Ru（p-cym）}部分的配位显著增强了整个络合物的活性。事实上，发现配合物4 [Ru-2（p-cym）（2）（L4）（2）]Cl-2是整个系列中活性最高的试剂，并对其进行了进一步的研究（以及配合物1用于比较）。关于作用模式，1和4的细胞死亡机制似乎与凋亡过程相关，并且它们与微管蛋白（参与细胞周期）和整合素（参与细胞骨架形成）强烈相互作用。作为其药代动力学的方法，评估了1和4与人血清白蛋白（HSA）的相互作用。根据圆二色光谱数据，提出了4与HSA结合的定量模型，并通过荧光实验进行了验证。Forster共振能量转移和荧光猝灭模型提供了4到单独的Trp 214残基的距离。重要的是，HSA结合增强了4的细胞毒性，并且与HSA结合数据良好相关。我们的研究结果一致表明，[Ru-2（p-cymene）（2）（L4）（2）]Cl-2作为一种有前景的金属药物用于癌症化疗是相当有前途的。
Four complexes combining the {Ru(p-cym)} moiety (p-cym = para-cymene) with thiosemicarbazone (TSC) ligands containing the 5-nitrofuryl pharmacophore were investigated in vitro for their properties as prospective anti-tumour agents. The compounds are dimeric structures of general formula [Ru-2(p-cym)(2)(L)(2)]-X-2 where X = Cl-, PF6- and L = deprotonated 5-nitrofuraldehyde TSC (L1), and the N-methyl (L2), N-ethyl (L3) and N-phenyl (L4) derivatives. The precursor [RuCl2(p-cym)](2), all TSC ligands L1-L4 and their corresponding complexes 1-4 were screened in vitro for their cytotoxicity against a range of human cancer cell lines (HL-60 acute promyelocytic leukemia, A2780 ovarian adenocarcinoma, MCF7 breast adenocarcinoma and PC3 grade IV prostate carcinoma). While the precursor complex was found to be inactive and L4 exhibited moderate activity only in the MCF7 cell line, the coordination of L4 to the {Ru(p-cym)} moiety remarkably enhanced the activity of the whole complex. In fact, complex 4 [Ru-2(p-cym)(2)(L4)(2)]Cl-2 was found to be the most active agent of the whole series, and was studied further (as well as complex 1 for comparison). Concerning the mode of action, the mechanism of cell death for both 1 and 4 seemed to be related to apoptotic processes, and they strongly interacted with tubulin (involved in the cell cycle) and with integrin (involved in the cytoskeleton formation). As an approach to their pharmacokinetics, the interaction of 1 and 4 with human serum albumin (HSA) was assessed. A quantitative model for the binding of 4 to HSA is proposed from Circular Dichroism data, and validated by fluorescence results. Models of Forster resonance energy transfer and fluorescence quenching afforded the distance of 4 to the lone Trp214 residue. Importantly, HSA binding enhanced the cytotoxicity of 4 and correlated well with the HSA binding data. Our results consistently indicate that [Ru-2(p-cymene)(2)(L4)(2)]Cl-2 is quite promising as a prospective metallodrug for cancer chemotherapy.