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首页> 外文期刊>Chemistry: A European journal >Spectroelectrochemical and computational studies on the mechanism of hypoxia selectivity of copper radiopharmaceuticals
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Spectroelectrochemical and computational studies on the mechanism of hypoxia selectivity of copper radiopharmaceuticals

机译：铜放射性药物缺氧选择性机理的光谱电化学和计算研究

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Detailed chemical, spectroelectrochemical and computational studies have been used to investigate the mechanism of hypoxia selectivity of a range of copper radiopharmaceuticals. A revised mechanism involving a delicate balance between cellular uptake, intracellular reduction, reoxidation, protonation and ligand dissociation is proposed. This mechanism accounts for observed differences in the reported cellular uptake and washout of related copper bis(thiosemicarbazonato) complexes. Three copper and zinc complexes have been characterised by X-ray crystallography and the redox chemistry of a series of copper complexes has been investigated by using electronic absorption and EPR spectroelectrochemistry. Time-dependent density functional theory (TDDFT) calculations have also been used to probe the electronic structures of intermediate species and assign the electronic absorption spectra. DFT calculations also show that one-electron oxidation is ligand-based, leading to the formation of cationic triplet species. In the absence of protons, metal-centred one-electron reduction gives the reduced anionic copper(I) species, [Cu(I)ATSM](-), and for the first time it is shown that molecular oxygen can reoxidise this anion to give the neutral, lipophilic parent complexes, which can wash out of cells. The electrochemistry is pH dependent and in the presence of stronger acids both chemical and electrochemical reduction leads to quantitative and rapid dissociation of copper(I) ions from the mono- or diprotonated complexes, [Cu(I)ATSMH] and [Cu(I)ATSMH(2)](+). In addition, a range of protonated intermediate species have been identified at lower acid concentrations. The one-electron reduction potential, rate of reoxidation of the copper(I) anionic species and ease of protonation are dependent on the structure of the ligand, which also governs their observed behaviour in vivo.
机译：详细的化学，光谱电化学和计算研究已用于研究一系列铜放射性药物的低氧选择性机制。提出了一种修正的机制，涉及细胞摄取，细胞内还原，再氧化，质子化和配体解离之间的微妙平衡。该机制解释了所报道的相关铜双（硫代半碳氮杂铜）络合物的细胞摄取和洗脱的差异。 X射线晶体学表征了三种铜和锌配合物，并通过电子吸收和EPR光谱电化学研究了一系列铜配合物的氧化还原化学。随时间变化的密度泛函理论（TDDFT）计算也已用于探测中间物种的电子结构并分配电子吸收光谱。 DFT计算还显示单电子氧化是基于配体的，导致形成阳离子三重态物质。在没有质子的情况下，以金属为中心的单电子还原可得到还原的阴离子铜（I）物种[Cu（I）ATSM]（-），并且首次表明分子氧可以将该阴离子重新氧化为产生中性，亲脂的母体复合物，可以将其洗出细胞。电化学取决于pH值，并且在强酸的存在下，化学还原和电化学还原都会导致铜（I）离子从单质子化或双质子化配合物[Cu（I）ATSMH]和[Cu（I） ATSMH（2）]（+）。此外，在较低的酸浓度下已鉴定出一系列质子化的中间物种。单电子还原电位，阴离子铜（I）的再氧化速率和质子化的容易程度取决于配体的结构，这也决定了它们在体内的行为。

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