Istituto CNR di Chimica Biomolecolare, Trav. La Crucca 3, I-07040 Sassari, Italy.
Dalton Trans. 2017 Jul 18;46(28):8950-8967. doi: 10.1039/c7dt00943g.
The first report on the anti-cancer activity of the compound Metvan, [VO(Mephen)(SO)], where Mephen is 4,7-dimethyl-1,10-phenanthroline, dates back to 2001. Although it was immediately identified as one of the most promising multitargeted anti-cancer V compounds, no development on the medical experimentation was carried out. One of the possible reasons is the lack of information on its speciation in aqueous solution and its thermodynamic stability, factors which influence the transport in the blood and the final form which reaches the target organs. To fill this gap, in this work the speciation of Metvan in aqueous solution and human blood was studied by instrumental (EPR, electronic absorption spectroscopy, ESI-MS and ESI-MS/MS), analytical (pH-potentiometry) and computational (DFT) methods. The results suggested that Metvan transforms at physiological pH into the hydrolytic species cis-[VO(Mephen)(OH)] and that both citrate and proteins (transferrin and albumin in the blood serum, and hemoglobin in the erythrocytes) form mixed complexes, denoted [VO(Mephen)(citrH)] and VO-Mephen-Protein with the probable binding of His-N donors. The measurements with erythrocytes suggest that Metvan is able to cross their membrane forming mixed species VO-Mephen-Hb. The redox stability in cell culture medium was also examined, showing that ca. 60% is oxidized to V after 5 h. Overall, the speciation of Metvan in the blood mainly depends on the V concentration: when it is larger than 50 μM, [VO(Mephen)(citrH)] and VO-Mephen-Protein are the major species, while for concentrations lower than 10 μM, (VO)(hTf) is formed and Mephen is lost. Therefore, it is plausible that the pharmacological activity of Metvan could be due to the synergic action of free Mephen, and VO and VO/VO species.
该化合物 Metvan（[VO（Mephen）（SO）]）的抗癌活性的首次报道可追溯到 2001 年。尽管它立即被确定为最有前途的多靶抗癌 V 化合物之一，但在医学实验方面没有进行任何开发。其中一个可能的原因是缺乏其在水溶液中的形态和热力学稳定性的信息，这些因素会影响在血液中的运输以及最终到达靶器官的形式。为了填补这一空白，本工作通过仪器（EPR、电子吸收光谱、ESI-MS 和 ESI-MS/MS）、分析（pH 电位滴定法）和计算（DFT）方法研究了 Metvan 在水溶液和人血液中的形态。结果表明，Metvan 在生理 pH 值下转化为水解物种 cis-[VO（Mephen）（OH）]，并且柠檬酸和蛋白质（血清中的转铁蛋白和白蛋白，以及红细胞中的血红蛋白）形成混合络合物，标记为[VO（Mephen）（citrH）]和 VO-Mephen-Protein，可能与 His-N 供体结合。与红细胞的测量表明，Metvan 能够穿过它们的膜形成混合物种 VO-Mephen-Hb。还检查了细胞培养介质中的氧化还原稳定性，表明在 5 小时后约有 60%被氧化为 V。总体而言，Metvan 在血液中的形态主要取决于 V 浓度：当浓度大于 50 μM 时，[VO（Mephen）（citrH）]和 VO-Mephen-Protein 是主要物种，而浓度低于 10 μM 时，形成（VO）（hTf），并失去 Mephen。因此，Metvan 的药理活性可能归因于游离 Mephen、VO 和 VO/VO 物种的协同作用。
