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Type: Journal article
Title: Cellular fates of manganese(II) pentaazamacrocyclic superoxide dismutase (SOD) mimetics: fluorescently labeled MnSOD mimetics, X-ray absorption spectroscopy, and X-ray fluorescence microscopy studies
Author: Weekley, C.
Kenkel, I.
Lippert, R.
Wei, S.
Lieb, D.
Cranwell, T.
Wedding, J.
Zillmann, A.
Rohr, R.
Filipovic, M.
Ivanović-Burmazović, I.
Harris, H.
Citation: Inorganic Chemistry: including bioinorganic chemistry, 2017; 56(11):6076-6093
Publisher: ACS Publications
Issue Date: 2017
ISSN: 0020-1669
Statement of
Claire M. Weekley , Isabell Kenkel, Rainer Lippert, Shengwei Wei, Dominik Lieb, Tiffanny Cranwell, Jason L. Wedding, Annika S. Zillmann, Robin Rohr, Milos R. Filipovic, Ivana Ivanović-Burmazović and Hugh H. Harris
Abstract: Manganese(II) pentaazamacrocyclic complexes (MnPAMs) can act as small-molecule mimics of manganese superoxide dismutase (MnSOD) with potential therapeutic application in conditions linked to oxidative stress. Previously, the in vitro mechanism of action has been determined, their activity has been demonstrated in cells, and some representatives of this class of MnSOD mimetics have entered clinical trials. However, MnPAM uptake, distribution, and metabolism in cells are largely unknown. Therefore, we have used X-ray fluorescence microscopy (XFM) and X-ray absorption spectroscopy (XAS) to study the cellular fate of a number of MnPAMs. We have also synthesized and characterized fluorescently labeled (pyrene and rhodamine) manganese(II) pyane [manganese(II) trans-2,13-dimethyl-3,6,9,12,18-pentaazabicyclo[12.3.1]octadeca-1(18),14,16-triene] derivatives and investigated their utility for cellular imaging of MnPAMs. Their SOD activity was determined via a direct stopped-flow technique. XFM experiments show that treatment with amine-based manganese(II) pyane type pentaazamacrocycles leads to a 10-100-fold increase in the overall cellular manganese levels compared to the physiological levels of manganese in control cells. In treated cells in general, manganese was distributed throughout the cell body, with a couple of notable exceptions. The lipophilicity of the MnPAMs, examined by partitioning in octanol-buffer system, was a good predictor of the relative cellular manganese levels. Analysis of the XAS data of treated cells revealed that some fraction of amine-based MnPAMs taken up by the cells remained intact, with the rest transformed into SOD-active manganese(II) phosphate. Higher phosphate binding constants, determined from the effect of the phosphate concentration on in vitro SOD activity, were associated with more extensive metabolism of the amine-based MnPAMs to manganese(II) phosphate. In contrast, the imine-based manganese(II) pydiene complex that is prone to hydrolysis was entirely decomposed after uptake and free manganese(II) was oxidized to a manganese(III) oxide type species, in cytosolic compartments, possibly mitochondria. Complex stability constants (determined for some of the MnPAMs) are less indicative of the cellular fate of the complexes than the corresponding phosphate binding constants.
Keywords: Tumor Cells, Cultured
Organometallic Compounds
Macrocyclic Compounds
Superoxide Dismutase
Microscopy, Fluorescence
Biomimetic Materials
X-Ray Absorption Spectroscopy
Rights: © 2017 American Chemical Society
DOI: 10.1021/acs.inorgchem.6b03073
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