康奈尔大学Justin J. Wilson | 含二茂铁的MCU抑制剂Ru265类似物具有更强细胞渗透性
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ICF Emerging Investigator Series
Mitochondrial calcium (mCa2+) plays an important role in a wide range of biological processes that are critical for cellular function. The uptake of mCa2+ is enforced by the mitochondrial calcium uniporter (MCU), a highly selective inwardly rectifying Ca2+ channel. Elevated mCa2+ levels are associated with a wide range of pathological conditions, including ischemia-reperfusion injury, cancer, and neurodegenerative disorders. Given the involvement of mCa2+ in these human diseases, there has been a growing interest in developing compounds that can inhibit the MCU to prevent mCa2+ overload. The highly hydrophilic diruthenium nitrido-bridged ruthenium compound, Ru265, is the most potent MCU inhibitor known to date.
Recently, the group of Prof. Justin Wilson from Cornell University has reported two novel MCU inhibitors, RuOFc and RuOBz, which are analogues of Ru265 that has been derivatized with the lipophilic ferrocenecarboxylate and benzoate ligands, respectively (Chart 1). Both compounds were synthesized and fully characterized by NMR spectroscopy, infrared spectroscopy and X-ray crystallography (Figure 1). Both compounds exhibit significant retention on the reverse-phase HPLC column. In contrast, Ru265 elutes within the dead time of the column. These results indicate that RuOFc and RuOBz are significantly more lipophilic than Ru265. Using an established RP-HPLC protocol, the log P values of RuOFc and RuOBz were determined to be 2.0 and 0.6, respectively.
Chart 1 Structures of Ru-based MCU inhibitors.
Figure 1 Crystal structures of RuOBz and RuOFc. Thermal ellipsoids are shown at the 50% probability level. Solvents and counterions are omitted for clarity.
Encouraged by the enhanced physical properties of these compounds, the researchers proceeded to evaluate their biological properties. In intact HEK293T cells, RuOBz is taken up by cells and inhibits the MCU to a similar extent as Ru265. RuOFc, however, exhibits a 10-fold increase in cellular uptake over Ru265. The dramatic improvement in cell permeability is most likely facilitated by the high lipophilicity of the ferrocene functional group. Finally, the MCU inhibitory activities of these complexes were examined in intact HeLa cells. RuOBz is able to inhibit mCa2+ uptake in intact cells to a comparable extent as Ru265. By contrast, RuOFc exhibits a modest yet statistically significant increase in inhibitory activity compared to Ru265, a property that may be a consequence of its enhanced cellular uptake (Figure 2).
Figure 2 Left: representative mCa2+ uptake after addition of 100 μM histamine in HeLa cells that were pretreated with or without Ru265, RuOBz, or RuOFc (50 μM) for 3.5 h and then loaded with 2 μM Rhod2AM. The arrow indicates the time of histamine addition. Right: Peak F/F0 in response to the histamine addition. Data represent mean ± standard deviation (SD).
Overall, the authors demonstrated that the cellular uptake of Ru265-based MCU inhibitors can be substantially improved by incorporating lipophilic ligands at the axial positions. This axial functionalization strategy expands the toolkit of MCU inhibitors that can be fine-tuned for specific applications in managing pathological conditions related to dysregulation of mCa2+ levels.
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A ferrocene-containing analogue of the MCU inhibitor Ru265 with increased cell permeability
Zhouyang Huang, Jesse A. Spivey, Samantha N. MacMillan and Justin J. Wilson
Inorg. Chem. Front., 2023, Advance Article
https://doi.org/10.1039/D2QI02183H
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通讯作者简介
Prof. Justin J. Wilson
Cornell University
Justin Wilson obtained his B.S. in chemistry from U.C. Berkeley in 2008 and his PhD in inorganic chemistry in 2013 from the Massachusetts Institute of Technology working in the lab of Professor Stephen J. Lippard. Following a position as a Seaborg Institute Postdoctoral Fellow at Los Alamos National Laboratory, he began his independent career as a faculty member in the Department of Chemistry and Chemical Biology at Cornell University in 2015.
During his independent career at Cornell, he has received numerous awards including the 2019 Cottrell Scholar Award, the 2019 ACS Jonathan L. Sessler Award for Emerging Leaders in Bioinorganic and Medicinal Inorganic Chemistry, the 2020 Stiefel Lecture Award at the Metals in Biology Gordon Research Conference, and the 2022 ACS National Award Harry Gray Award for Creative Work in Inorganic Chemistry by a Young Investigator.
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