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Linear gold(I) complex with tris-(2-carboxyethyl)phosphine (TCEP): Selective antitumor activity and inertness toward sulfur proteins
Journal of Inorganic Biochemistry ( IF 3.9 ) Pub Date : 2018-04-14
S.Q. Gomes, L. Vitoriano, E.G.R. de Arruda, A.L.T.G. Ruiz, T. Candido, J.E. de Carvalho, W.R. Lustri, C. Abbehausen

The search for modulating ligand substitution reaction in gold complexes is essential to find new active metallo compounds for medical applications. In this work, a new linear and hydrosoluble goldI complex with tris-(2-carboxyethylphosphine) (TCEP) was prepared and the crystal structure solved by single crystal X-ray diffraction. The AuI coordinates linearly to two phosphines by the phosphorus atoms. Spectroscopic evaluation by 1H, 13C, 31P NMR in solid and solution state, infrared, mass spectrometry is also reported. In vitro growth inhibition (GI50) in a panel of nine tumorigenic and one non-tumorigenic cell lines demonstrated the complex is highly selective to ovarium adenocarcinoma (OVCAR-3) with GI50 of 3.04 nmol mL−1. Biophysical evaluation with the sulfur-rich amino acids and proteins showed the compound does not interact with two types of zinc fingers, bovine serum albumin, N-acetyl-l-cysteine and also l-histidine, revealing to be inert to ligand substitution reactions with these molecules. The compound also showed no antibacterial activity. Besides, it inhibits 15% of the activity of a mixture of serine-β-lactamase and metallo-β-lactamase from Bacillus cereus in the enzymatic activity assay, similarly to EDTA. These results suggest AuTCEP is selective to MBL but the cell uptake is hindered, and the compound does not reach the periplasmic space of Gram-positive bacteria. The unique inert behavior of AuTCEP is interesting to the field and represent the modulation of the reactivity through coordination chemistry to decrease the toxicity associated with AuI complexes and its lack of specificity, generating very selective compounds.



中文翻译:

具有三-(2-羧乙基)膦(TCEP)的线性金(I)配合物:对硫蛋白的选择性抗肿瘤活性和惰性

在金络合物中寻找调节配体取代反应的方法对于寻找用于医学应用的新型活性金属化合物至关重要。在这项工作中,制备了具有三-(2-羧乙基膦)(TCEP)的新型线性和水溶性金I络合物,并通过单晶X射线衍射解析了晶体结构。Au I通过磷原子线性配位至两个膦。还报道了通过1 H,13 C,31 P NMR在固态和溶液状态下的光谱评估,红外光谱,质谱。体外生长抑制(GI 50)在9种致瘤细胞和一种非致瘤细胞系中显示,该复合物对卵巢腺癌(OVCAR-3)具有高度选择性,GI 50为3.04 nmol mL -1。用富含硫的氨基酸和蛋白质进行的生物物理评估表明,该化合物与两种类型的锌指(牛血清白蛋白,N-乙酰基-1-半胱氨酸和l-组氨酸)不相互作用,表明对配体取代反应呈惰性这些分子。该化合物也没有显示抗菌活性。此外,它抑制蜡样芽胞杆菌的丝氨酸-β-内酰胺酶和金属-β-内酰胺酶混合物的活性的15%。在酶活性测定中,类似于EDTA。这些结果表明AuTCEP对MBL具有选择性,但阻碍了细胞摄取,并且该化合物未到达革兰氏阳性细菌的周质空间。AuTCEP的独特惰性行为在该领域引起了人们的兴趣,它代表通过配位化学调节反应性,以降低与Au I复合物相关的毒性及其缺乏特异性,从而产生非常选择性的化合物。

更新日期:2018-04-25
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