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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

Version 2 2024-06-04, 08:06
Version 1 2018-04-18, 16:47
journal contribution
posted on 2024-06-04, 08:06 authored by KM Acevedo, David HayneDavid Hayne, LE McInnes, A Noor, C Duncan, D Moujalled, I Volitakis, A Rigopoulos, KJ Barnham, VL Villemagne, AR White, PS Donnelly
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 [ 64 Cu]Cu(gtspyr) has reasonable brain uptake but high liver uptake.

History

Journal

Journal of medicinal chemistry

Volume

61

Pagination

711-723

Location

Washington, D.C.

ISSN

0022-2623

eISSN

1520-4804

Language

eng

Publication classification

C Journal article, C1.1 Refereed article in a scholarly journal

Copyright notice

2017, American Chemical Society

Issue

3

Publisher

American Chemical Society