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Effect of Structural Modifications to Glyoxal-bis(thiosemicarbazonato)copper(II) Complexes on Cellular Copper Uptake, Copper-Mediated ATP7A Trafficking, and P-Glycoprotein Mediated Efflux
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-08 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01158 Karla M. Acevedo , David J. Hayne , Lachlan E. McInnes , Asif Noor , Clare Duncan , Diane Moujalled , Irene Volitakis , Angela Rigopoulos 1 , Kevin J. Barnham , Victor L. Villemagne 2 , Anthony R. White , Paul S. Donnelly
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-08 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01158 Karla M. Acevedo , David J. Hayne , Lachlan E. McInnes , Asif Noor , Clare Duncan , Diane Moujalled , Irene Volitakis , Angela Rigopoulos 1 , Kevin J. Barnham , Victor L. Villemagne 2 , Anthony R. White , Paul S. Donnelly
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Bis(thiosemicarbazonato)copper(II) complexes are of interest as potential therapeutics for cancer and neurodegenerative diseases as well as imaging agents for positron emission tomography (PET). The cellular uptake of six bis(thiosemcarbazonato)copper(II)complexes derived from glyoxal, with different functional groups Cu(gtsx) where x = different functional groups, was investigated in SKOV-3, HEK293, and HEK293 P-gp cell lines. Treatment of the cells with the copper complexes increased intracellular copper and increased levels of p-ERK due to activation of the Ras-Raf-MEK-ERK pathway. Treatment of SKOV-3 cells with low concentrations (μM) of two of the copper complexes led to trafficking of the endogenous copper transporter ATP7A from the Golgi network to the cell membrane. Experiments in HEK293 and HEK293-P-gp cells suggest that Cu(gtsm) and Cu(gtse) are substrates for the P-gp efflux protein but the complex with a pyrrolidine functional group, Cu(gtspyr), is not. A PET experiment in mice showed that [64Cu]Cu(gtspyr) has reasonable brain uptake but high liver uptake.
中文翻译：
乙二醛-双（硫代半碳氮杂）铜（II）配合物的结构修饰对细胞吸收铜，铜介导的ATP7A转运和P-糖蛋白介导的外排的影响
双（硫代半碳氮杂）铜（II）络合物作为癌症和神经退行性疾病的潜在治疗剂以及正电子发射断层扫描（PET）的显像剂备受关注。六个双细胞摄取（thiosemcarbazonato）铜（II）配合物从乙二醛衍生的，具有不同官能团的Cu（GTS X），其中X在SKOV-3，HEK293和HEK293 P-gp细胞系中研究了不同的官能团。由于Ras-Raf-MEK-ERK途径的激活，用铜络合物处理细胞增加了细胞内铜和增加了p-ERK的水平。用低浓度（μM）的两种铜络合物处理SKOV-3细胞导致内源性铜转运蛋白ATP7A从高尔基网络转运到细胞膜。在HEK293和HEK293-P-gp细胞中进行的实验表明，Cu（gtsm）和Cu（gtse）是P-gp外排蛋白的底物，但具有吡咯烷官能团Cu（gtspyr）的复合物不是。在小鼠中进行的PET实验表明，[ 64 Cu] Cu（gtspyr）具有合理的脑摄取，但肝摄取高。
更新日期：2018-01-08
中文翻译：
乙二醛-双（硫代半碳氮杂）铜（II）配合物的结构修饰对细胞吸收铜，铜介导的ATP7A转运和P-糖蛋白介导的外排的影响
双（硫代半碳氮杂）铜（II）络合物作为癌症和神经退行性疾病的潜在治疗剂以及正电子发射断层扫描（PET）的显像剂备受关注。六个双细胞摄取（thiosemcarbazonato）铜（II）配合物从乙二醛衍生的，具有不同官能团的Cu（GTS X），其中X在SKOV-3，HEK293和HEK293 P-gp细胞系中研究了不同的官能团。由于Ras-Raf-MEK-ERK途径的激活，用铜络合物处理细胞增加了细胞内铜和增加了p-ERK的水平。用低浓度（μM）的两种铜络合物处理SKOV-3细胞导致内源性铜转运蛋白ATP7A从高尔基网络转运到细胞膜。在HEK293和HEK293-P-gp细胞中进行的实验表明，Cu（gtsm）和Cu（gtse）是P-gp外排蛋白的底物，但具有吡咯烷官能团Cu（gtspyr）的复合物不是。在小鼠中进行的PET实验表明，[ 64 Cu] Cu（gtspyr）具有合理的脑摄取，但肝摄取高。
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