The transmembrane protein known as the mitochondrial calcium uniporter(MCU)mediates the influx of calcium ions(Ca^(2+))into the mitochondrial matrix.An overload of mitochondrial Ca^(2+)(mCa^(2+))is directly linked to ...The transmembrane protein known as the mitochondrial calcium uniporter(MCU)mediates the influx of calcium ions(Ca^(2+))into the mitochondrial matrix.An overload of mitochondrial Ca^(2+)(mCa^(2+))is directly linked to damaging effects in pathological conditions.Therefore,inhibitors of the MCU are important chemical biology tools and therapeutic agents.Here,two new analogues of previously reported Ru-and Os-based MCU inhibitors Ru265 and Os245,of the general formula[(C_(10)H_(15)CO_(2))M(NH_(3))_(4)(μ-N)M(NH_(3))_(4)(O_(2)CC_(10)H_(15))](CF_(3)SO_(3))_(3),where M=Ru(1)or Os(2),are reported.These analogues bear adamantane functional groups,which were installed to act as vips for the host molecule cucurbit-[7]-uril(CB[7]).These complexes were characterized and analyzed for their efficiency as vips for CB[7].As shown through a variety of spectroscopic techniques,each adamantane ligand is encapsulated into one CB[7],affording a supramolecular complex of 1:2 stoichiometry.The biological effects of these compounds in the presence and absence of two equiv.CB[7]were assessed.Both complexes 1 and 2 exhibit enhanced cellular uptake compared to the parent compounds Ru265 and Os245,and their uptake is increased further in the presence of CB[7].Compared to Ru265 and Os245,1 and 2 are less potent as mCa^(2+)uptake inhibitors in permeabilized cell models.However,in intact cell systems,1 and 2 inhibit the MCU at concentrations as low as 1μM,marking an advantage over Ru265 and Os245 which require an order of magnitude higher doses for similar biological effects.The presence of CB[7]did not affect the inhibitory properties of 1 and 2.Experiments in primary cortical neurons showed that 1 and 2 can elicit protective effects against oxygen-glucose deprivation at lower doses than those required for Ru265 or Os245.At low concentrations,the protective effects of 1 were modulated by CB[7],suggesting that supramolecular complex formation can play a role in these biological conditions.The in vivo biocompatibility of 1 was investigated in mice.The intraperitoneal administration of these compounds and their CB[7]complexes led to time-dependent induction of seizures with no protective effects elicited by CB[7].This work demonstrates the potential for supramolecular interactions in the development of MCU inhibitors.展开更多
基金supported by the College of Arts&Sciences at Cornell UniversityDr Ivan Keresztes is thanked for his assistance with all NMR experiments+6 种基金This work made use of the Cornell NMR facility,which is supported in part by the NSF(CHE-1531632)the Cornell Institute of Biotechnology Imaging Facility,which is supported in part by the National Institute of Health(NIH)under award number S10RR025502funded in part by the Faculty Development Fund and Startup Funds at the University of San Franciscofunded in part through the Whitehead Summer Research Fellowshipsupported by the Heart and Stroke Foundation of Canada(G-22-0031944,GSR)the Dalhousie University Brain Repair Centre(Knowledge and Translation GrantGSR).
文摘The transmembrane protein known as the mitochondrial calcium uniporter(MCU)mediates the influx of calcium ions(Ca^(2+))into the mitochondrial matrix.An overload of mitochondrial Ca^(2+)(mCa^(2+))is directly linked to damaging effects in pathological conditions.Therefore,inhibitors of the MCU are important chemical biology tools and therapeutic agents.Here,two new analogues of previously reported Ru-and Os-based MCU inhibitors Ru265 and Os245,of the general formula[(C_(10)H_(15)CO_(2))M(NH_(3))_(4)(μ-N)M(NH_(3))_(4)(O_(2)CC_(10)H_(15))](CF_(3)SO_(3))_(3),where M=Ru(1)or Os(2),are reported.These analogues bear adamantane functional groups,which were installed to act as vips for the host molecule cucurbit-[7]-uril(CB[7]).These complexes were characterized and analyzed for their efficiency as vips for CB[7].As shown through a variety of spectroscopic techniques,each adamantane ligand is encapsulated into one CB[7],affording a supramolecular complex of 1:2 stoichiometry.The biological effects of these compounds in the presence and absence of two equiv.CB[7]were assessed.Both complexes 1 and 2 exhibit enhanced cellular uptake compared to the parent compounds Ru265 and Os245,and their uptake is increased further in the presence of CB[7].Compared to Ru265 and Os245,1 and 2 are less potent as mCa^(2+)uptake inhibitors in permeabilized cell models.However,in intact cell systems,1 and 2 inhibit the MCU at concentrations as low as 1μM,marking an advantage over Ru265 and Os245 which require an order of magnitude higher doses for similar biological effects.The presence of CB[7]did not affect the inhibitory properties of 1 and 2.Experiments in primary cortical neurons showed that 1 and 2 can elicit protective effects against oxygen-glucose deprivation at lower doses than those required for Ru265 or Os245.At low concentrations,the protective effects of 1 were modulated by CB[7],suggesting that supramolecular complex formation can play a role in these biological conditions.The in vivo biocompatibility of 1 was investigated in mice.The intraperitoneal administration of these compounds and their CB[7]complexes led to time-dependent induction of seizures with no protective effects elicited by CB[7].This work demonstrates the potential for supramolecular interactions in the development of MCU inhibitors.
