Biomimetic Model Featuring the NH Proton and Bridging Hydride Related to a Proposed Intermediate in Enzymatic H₂ Production by Fe-Only Hydrogenase

Iron azadithiolate phosphine-substituted complex and its protonated species featuring the NH proton and/or bridging Fe hydride, [Fe2(μ-S(CH2)2NnPr(H)m(CH2)2S)(μ-H)n(CO)4(PMe3)2]2(2m+2n)+ (1, m = n = 0; [1−2HN]2+, m = 1, n = 0; [1−2HN2HFe]4+, m = n = 1), are prepared to mimic the active site of Fe-only hydrogenase. X-ray crystallographic analyses of these three complexes reveal that two diiron subunits are linked by two azadiethylenethiolate bridges to construct a dimer-of-dimer structure. 31P NMR spectroscopy confirms two trimethylphosphine ligands within the diiron moiety are arranged in the apical/basal configuration, which is consistent with the solid-state structural characterization. Deprotonation of the NH proton in [1−2HN]2+ and [1−2HN2HFe]4+ occurs in the presence of triethanolamine (TEOA), which generates 1 and [1−2HFe]2+, respectively. Deprotonation of the Fe hydride is accomplished by addition of bistriphenylphosphineimminium chloride ([PPN]Cl). It is observed that the Fe hydride species, [1−2HFe]2+, is a kinetic product which converts to its thermodynamically stable tautomer, [1−2HN]2+, in solution, as evidenced by IR and NMR spectroscopy. The pKa values of the aza nitrogen and the diiron sites are estimated to be 8.9−15.9 and [1−2HN2HFe]4+ has been observed to evolve H2 electrocatalytically at a mild potential (−1.42 V vs Fc/Fc+) in CH3CN solution. Catalysis of [1−2HN2HFe]4+ is found to be as efficient as that of the related diiron azadithiolate complexes. In the absence of a proton source, [1−2HN2HFe]4+ undergoes four irreversible reduction processes at −1.26, −1.42, −1.82, and −2.43 V, which are attributed to the reduction events from [1−2HN2HFe]4+, [1−2HFe]2+, [1−2HN]2+, and 1, respectively, according to bulk electrolysis and voltammetry in combination of titration experiments with acids

Biomimetic Model Featuring the NH Proton and Bridging Hydride Related to a Proposed Intermediate in Enzymatic H₂ Production by Fe-Only Hydrogenase

Iron azadithiolate phosphine-substituted complex and its protonated species featuring the NH proton and/or bridging Fe hydride, [Fe2(μ-S(CH2)2NnPr(H)m(CH2)2S)(μ-H)n(CO)4(PMe3)2]2(2m+2n)+ (1, m = n = 0; [1−2HN]2+, m = 1, n = 0; [1−2HN2HFe]4+, m = n = 1), are prepared to mimic the active site of Fe-only hydrogenase. X-ray crystallographic analyses of these three complexes reveal that two diiron subunits are linked by two azadiethylenethiolate bridges to construct a dimer-of-dimer structure. 31P NMR spectroscopy confirms two trimethylphosphine ligands within the diiron moiety are arranged in the apical/basal configuration, which is consistent with the solid-state structural characterization. Deprotonation of the NH proton in [1−2HN]2+ and [1−2HN2HFe]4+ occurs in the presence of triethanolamine (TEOA), which generates 1 and [1−2HFe]2+, respectively. Deprotonation of the Fe hydride is accomplished by addition of bistriphenylphosphineimminium chloride ([PPN]Cl). It is observed that the Fe hydride species, [1−2HFe]2+, is a kinetic product which converts to its thermodynamically stable tautomer, [1−2HN]2+, in solution, as evidenced by IR and NMR spectroscopy. The pKa values of the aza nitrogen and the diiron sites are estimated to be 8.9−15.9 and [1−2HN2HFe]4+ has been observed to evolve H2 electrocatalytically at a mild potential (−1.42 V vs Fc/Fc+) in CH3CN solution. Catalysis of [1−2HN2HFe]4+ is found to be as efficient as that of the related diiron azadithiolate complexes. In the absence of a proton source, [1−2HN2HFe]4+ undergoes four irreversible reduction processes at −1.26, −1.42, −1.82, and −2.43 V, which are attributed to the reduction events from [1−2HN2HFe]4+, [1−2HFe]2+, [1−2HN]2+, and 1, respectively, according to bulk electrolysis and voltammetry in combination of titration experiments with acids

Biomimetic Model Featuring the NH Proton and Bridging Hydride Related to a Proposed Intermediate in Enzymatic H₂ Production by Fe-Only Hydrogenase

Iron azadithiolate phosphine-substituted complex and its protonated species featuring the NH proton and/or bridging Fe hydride, [Fe2(μ-S(CH2)2NnPr(H)m(CH2)2S)(μ-H)n(CO)4(PMe3)2]2(2m+2n)+ (1, m = n = 0; [1−2HN]2+, m = 1, n = 0; [1−2HN2HFe]4+, m = n = 1), are prepared to mimic the active site of Fe-only hydrogenase. X-ray crystallographic analyses of these three complexes reveal that two diiron subunits are linked by two azadiethylenethiolate bridges to construct a dimer-of-dimer structure. 31P NMR spectroscopy confirms two trimethylphosphine ligands within the diiron moiety are arranged in the apical/basal configuration, which is consistent with the solid-state structural characterization. Deprotonation of the NH proton in [1−2HN]2+ and [1−2HN2HFe]4+ occurs in the presence of triethanolamine (TEOA), which generates 1 and [1−2HFe]2+, respectively. Deprotonation of the Fe hydride is accomplished by addition of bistriphenylphosphineimminium chloride ([PPN]Cl). It is observed that the Fe hydride species, [1−2HFe]2+, is a kinetic product which converts to its thermodynamically stable tautomer, [1−2HN]2+, in solution, as evidenced by IR and NMR spectroscopy. The pKa values of the aza nitrogen and the diiron sites are estimated to be 8.9−15.9 and [1−2HN2HFe]4+ has been observed to evolve H2 electrocatalytically at a mild potential (−1.42 V vs Fc/Fc+) in CH3CN solution. Catalysis of [1−2HN2HFe]4+ is found to be as efficient as that of the related diiron azadithiolate complexes. In the absence of a proton source, [1−2HN2HFe]4+ undergoes four irreversible reduction processes at −1.26, −1.42, −1.82, and −2.43 V, which are attributed to the reduction events from [1−2HN2HFe]4+, [1−2HFe]2+, [1−2HN]2+, and 1, respectively, according to bulk electrolysis and voltammetry in combination of titration experiments with acids

Biomimetic Model Featuring the NH Proton and Bridging Hydride Related to a Proposed Intermediate in Enzymatic H₂ Production by Fe-Only Hydrogenase

Iron azadithiolate phosphine-substituted complex and its protonated species featuring the NH proton and/or bridging Fe hydride, [Fe2(μ-S(CH2)2NnPr(H)m(CH2)2S)(μ-H)n(CO)4(PMe3)2]2(2m+2n)+ (1, m = n = 0; [1−2HN]2+, m = 1, n = 0; [1−2HN2HFe]4+, m = n = 1), are prepared to mimic the active site of Fe-only hydrogenase. X-ray crystallographic analyses of these three complexes reveal that two diiron subunits are linked by two azadiethylenethiolate bridges to construct a dimer-of-dimer structure. 31P NMR spectroscopy confirms two trimethylphosphine ligands within the diiron moiety are arranged in the apical/basal configuration, which is consistent with the solid-state structural characterization. Deprotonation of the NH proton in [1−2HN]2+ and [1−2HN2HFe]4+ occurs in the presence of triethanolamine (TEOA), which generates 1 and [1−2HFe]2+, respectively. Deprotonation of the Fe hydride is accomplished by addition of bistriphenylphosphineimminium chloride ([PPN]Cl). It is observed that the Fe hydride species, [1−2HFe]2+, is a kinetic product which converts to its thermodynamically stable tautomer, [1−2HN]2+, in solution, as evidenced by IR and NMR spectroscopy. The pKa values of the aza nitrogen and the diiron sites are estimated to be 8.9−15.9 and [1−2HN2HFe]4+ has been observed to evolve H2 electrocatalytically at a mild potential (−1.42 V vs Fc/Fc+) in CH3CN solution. Catalysis of [1−2HN2HFe]4+ is found to be as efficient as that of the related diiron azadithiolate complexes. In the absence of a proton source, [1−2HN2HFe]4+ undergoes four irreversible reduction processes at −1.26, −1.42, −1.82, and −2.43 V, which are attributed to the reduction events from [1−2HN2HFe]4+, [1−2HFe]2+, [1−2HN]2+, and 1, respectively, according to bulk electrolysis and voltammetry in combination of titration experiments with acids

Development of Strigolactones as Novel Autophagy/Mitophagy Inhibitors against Colorectal Cancer Cells by Blocking the Autophagosome–Lysosome Fusion

Inhibition of autophagy has been widely viewed as a promising strategy for anticancer therapy. However, few effective and specific autophagy inhibitors have been reported. Herein, we described the design, synthesis, and biological characteristics of new analogues of strigolactones (SLs), an emerging class of plant hormones, against colorectal cancers. Among them, an enantiopure analogue 6 exerted potent and selective cytotoxicity against colorectal cancer cells, but not normal human colon mucosal epithelial cells, which were further confirmed by the plate colony formation assay. Moreover, it significantly inhibited tumor growth in an HCT116 xenograft mouse model with low toxicity. Mechanistically, it is associated with selective induction of cell apoptosis and cell cycle arrest. Remarkably, 6 acted as a potent autophagy/mitophagy inhibitor by selectively increasing the autophagic flux while blocking the autophagosome–lysosome fusion in HCT116 cells. This study features stereo-defined SLs as novel autophagy inhibitors with high cancer cell specificity, which paves a new path for anticolorectal cancer therapy

Development of Strigolactones as Novel Autophagy/Mitophagy Inhibitors against Colorectal Cancer Cells by Blocking the Autophagosome–Lysosome Fusion

Inhibition of autophagy has been widely viewed as a promising strategy for anticancer therapy. However, few effective and specific autophagy inhibitors have been reported. Herein, we described the design, synthesis, and biological characteristics of new analogues of strigolactones (SLs), an emerging class of plant hormones, against colorectal cancers. Among them, an enantiopure analogue 6 exerted potent and selective cytotoxicity against colorectal cancer cells, but not normal human colon mucosal epithelial cells, which were further confirmed by the plate colony formation assay. Moreover, it significantly inhibited tumor growth in an HCT116 xenograft mouse model with low toxicity. Mechanistically, it is associated with selective induction of cell apoptosis and cell cycle arrest. Remarkably, 6 acted as a potent autophagy/mitophagy inhibitor by selectively increasing the autophagic flux while blocking the autophagosome–lysosome fusion in HCT116 cells. This study features stereo-defined SLs as novel autophagy inhibitors with high cancer cell specificity, which paves a new path for anticolorectal cancer therapy

Development of Strigolactones as Novel Autophagy/Mitophagy Inhibitors against Colorectal Cancer Cells by Blocking the Autophagosome–Lysosome Fusion

Inhibition of autophagy has been widely viewed as a promising strategy for anticancer therapy. However, few effective and specific autophagy inhibitors have been reported. Herein, we described the design, synthesis, and biological characteristics of new analogues of strigolactones (SLs), an emerging class of plant hormones, against colorectal cancers. Among them, an enantiopure analogue 6 exerted potent and selective cytotoxicity against colorectal cancer cells, but not normal human colon mucosal epithelial cells, which were further confirmed by the plate colony formation assay. Moreover, it significantly inhibited tumor growth in an HCT116 xenograft mouse model with low toxicity. Mechanistically, it is associated with selective induction of cell apoptosis and cell cycle arrest. Remarkably, 6 acted as a potent autophagy/mitophagy inhibitor by selectively increasing the autophagic flux while blocking the autophagosome–lysosome fusion in HCT116 cells. This study features stereo-defined SLs as novel autophagy inhibitors with high cancer cell specificity, which paves a new path for anticolorectal cancer therapy

Secondary Coordination Sphere Interactions within the Biomimetic Iron Azadithiolate Complexes Related to Fe-Only Hydrogenase: Dynamic Measure of Electron Density about the Fe Sites

A series of iron azadithiolate complexes possessing an intramolecular secondary coordination sphere interaction and an ability to reduce HOAc at the potential near the first electron-transfer process are reported. A unique structural feature in which the aza nitrogen has its lone pair point toward the apical carbonyl carbon is observed in [Fe2(μ-S(CH2)2NR(CH2)2S)(CO)6−xLx]2 (R = nPr, x = 0, 1a; R = iPr, x = 0, 1b; R = nPr, L = PPh3, x = 1, 2; R = nPr, L = PnBu3, x = 1, 3) as biomimetic models of the active site of Fe-only hydrogenase. The presence of this weak N···C(COap) interaction provides electronic perturbation at the Fe center. The distance of the N···C(COap) contact is 3.497 Å in 1a. It increases by 0.455 Å in 2 when electronic density of the Fe site is slightly enriched by a weak σ-donating ligand, PPh3. A longer distance (4.040 Å) is observed for the PnBu3 derivative, 3. This N···C(COap) distance is thus a dynamic measure of electronic nature of the Fe2 core. Variation of electronic richness within the Fe2 moiety among the complexes reflects on their electrochemical response. Reduction of 2 is recorded at the potential of −2.17 V, which is 270 mV more negative than that of 1. Complex 3 requires additional 150 mV for the same reduction. Such cathodic shift results from CO substitution by phosphines. Electrocatalytic hydrogen production from HOAc by both kinds of complexes (all-CO and phosphine-substituted species) requires the potential close to that for reduction of the parent molecules in the absence of acids. The catalytic mechanism of 1a is proposed to involve proton uptake at the Fe0FeI redox level instead of the Fe0Fe0 level. This result is the first observation among the all-CO complexes with respect to electrocatalysis of HOAc

Secondary Coordination Sphere Interactions within the Biomimetic Iron Azadithiolate Complexes Related to Fe-Only Hydrogenase: Dynamic Measure of Electron Density about the Fe Sites

A series of iron azadithiolate complexes possessing an intramolecular secondary coordination sphere interaction and an ability to reduce HOAc at the potential near the first electron-transfer process are reported. A unique structural feature in which the aza nitrogen has its lone pair point toward the apical carbonyl carbon is observed in [Fe2(μ-S(CH2)2NR(CH2)2S)(CO)6−xLx]2 (R = nPr, x = 0, 1a; R = iPr, x = 0, 1b; R = nPr, L = PPh3, x = 1, 2; R = nPr, L = PnBu3, x = 1, 3) as biomimetic models of the active site of Fe-only hydrogenase. The presence of this weak N···C(COap) interaction provides electronic perturbation at the Fe center. The distance of the N···C(COap) contact is 3.497 Å in 1a. It increases by 0.455 Å in 2 when electronic density of the Fe site is slightly enriched by a weak σ-donating ligand, PPh3. A longer distance (4.040 Å) is observed for the PnBu3 derivative, 3. This N···C(COap) distance is thus a dynamic measure of electronic nature of the Fe2 core. Variation of electronic richness within the Fe2 moiety among the complexes reflects on their electrochemical response. Reduction of 2 is recorded at the potential of −2.17 V, which is 270 mV more negative than that of 1. Complex 3 requires additional 150 mV for the same reduction. Such cathodic shift results from CO substitution by phosphines. Electrocatalytic hydrogen production from HOAc by both kinds of complexes (all-CO and phosphine-substituted species) requires the potential close to that for reduction of the parent molecules in the absence of acids. The catalytic mechanism of 1a is proposed to involve proton uptake at the Fe0FeI redox level instead of the Fe0Fe0 level. This result is the first observation among the all-CO complexes with respect to electrocatalysis of HOAc

Table_8_Characterization of circRNA-Associated-ceRNA Networks Involved in the Pathogenesis of Postoperative Cognitive Dysfunction in Aging Mice.XLSX

Postoperative cognitive dysfunction (POCD) is a clinical entity associated with declined cognitive function following surgery. It occurs more frequently in elderly patients. Recent studies have shown that circRNA-associated-ceRNA networks, constructed based on interactions between circRNA-miRNA and miRNA-mRNA, provide key insight into the molecular mechanisms underlying the pathogenesis of several neurological diseases. However, the mechanism of POCD remains undetermined. In this study, laparotomies were performed under isoflurane anesthesia on young (2-month-old) and aging (17-month-old) male C57BL/6 mice. The results showed that the aging mice were more likely than the young mice to develop POCD. Subsequently, differentially expressed circRNAs, miRNAs, and mRNAs were characterized by RNA sequencing the hippocampi of young and aging mice under control and surgery conditions. Six circRNAs, 6 miRNAs, and 203 mRNAs were identified to construct the circRNA-associated-ceRNA network for the control condition, while 13 circRNAs, 8 miRNAs, and 189 mRNAs were used for the circRNA-associated-ceRNA network for the surgery condition. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of these two networks revealed that the circRNA-associated-ceRNA networks are involved in POCD pathogenesis though modulating the Wnt and VEGF signaling pathways, as well as neural processes associated with long-term synaptic depression and synaptic transmission. In particular, the mmu-miR-298-5P regulatory pathway identified in this study’s mouse model suggests that mm9_circ_009789- and mm9_circ_004229-associated-ceRNA networks as closely related to the occurrence of POCD through regulating PKC signaling pathway, neural cell apoptosis and glycolipid metabolism pathway. These findings provide possible insight into the role of the circRNA-associated-ceRNA networks, helping to unravel the complexity of the molecular pathogenesis of POCD.</p