Abstract
The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [Co(III)(salen)(acac)] complexes capable of up-regulating the ubiquitin ligase adaptor protein Ndfip1. Ndfip1 is a neuroprotective protein that is up-regulated in the brain after injury and functions in combination with Nedd4 ligases to ubiquitinate harmful proteins for removal. We previously showed that Ndfip1 can be increased in human neurons using CoCl(2) that is toxic at high concentration. Here we demonstrate a similar effect can be achieved by low concentrations of synthetic Co(III) complexes that are non-toxic and designed to be activated following cellular entry. Activation is achieved by intracellular reduction of Co(III) to Co(II) leading to release of Co(II) ions for Ndfip1 up-regulation. The cellular benefit of Ndfip1 up-regulation by Co(III) complexes includes demonstrable protection against cell death in SH-SY5Y cells during stress. In vivo, focal delivery of Co(III) complexes into the adult mouse brain was observed to up-regulate Ndfip1 in neurons. These results demonstrate that a cellular response pathway can be advantageously manipulated by chemical modification of metal complexes, and represents a significant step of harnessing low concentration metal complexes for therapeutic benefit.
Highlights
The designed compounds were effective at micromolar levels in their ability to up-regulate Nedd4 family interacting protein 1 (Ndfip1) expression
We have previously demonstrated that Ndfip1 can be up-regulated in response to metal-induced stress from iron and cobalt exposure, and the up-regulation is effective in protecting neurons from metal toxicity [3]
How this is achieved remains unclear, but one possibility is ubiquitin-mediated degradation of harmful proteins following binding to Ndfip1 [24]
Summary
The levels and regulation of metals in a cell can have a direct role on cell function and survival Metal ions such as CoII and FeII can stimulate the expression of the neuroprotective protein Nedd family interacting protein 1 (Ndfip1) in the brain [3]. We investigate the utility of nontoxic metal complexes for controlled intracellular delivery of cobalt to stimulate Ndfip expression This was based on the premise that the reactivity of metal ions can be modulated by the formation of coordination complexes, with a complexed. We report the design and synthesis of metal complexes capable of delivering cobalt ions into the cell that are bioactive at far lower concentrations than the free metal salts We demonstrate that this approach is capable of delivering low, but biologically effective levels of cobalt into the cell, resulting in Ndfip up-regulation with sustainable biological effects. Our approach centers on the coordination of metal ions with suitable ligands as a powerful means of drug design that can overcome traditional hurdles of metal toxicity without compromising biological outcomes
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