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The aggregation of amyloid ß (Aß) peptides is a significant hallmark of Alzheimer's disease (AD), and the detection of Aß aggregates and the inhibition of their formation are important for the diagnosis and treatment of AD, respectively. Herein, we report a series of benzothiazole-based Ir(III) complexes HN-1 to HN-8 that exhibit appreciable inhibition of Aß aggregation in vitro and in living cells. These Ir(III) complexes can induce a significant fluorescence increase when binding to Aß fibrils and Aß oligomers, while their measured log D values suggest these compounds could have enhanced blood-brain barrier (BBB) permeability. In vivo studies show that HN-1, HN-2, HN-3, and HN-8 successfully penetrate the BBB and stain the amyloid plaques in AD mouse brains after a 10-day treatment, suggesting that these Ir(III) complexes could act as lead compounds for AD therapeutic and diagnostic agent development.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Benzotiazoles , Complejos de Coordinación , Iridio , Agregado de Proteínas , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Iridio/química , Iridio/farmacología , Animales , Ratones , Benzotiazoles/química , Benzotiazoles/farmacología , Humanos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico , Agregado de Proteínas/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , TiazolesRESUMEN
Ferrocene is one of the most common electron donors, and mapping its ligand-field excited states is critical to designing donor-acceptor (D-A) molecules with long-lived charge transfer states. Although 3(d-d) states are commonly invoked in the photophysics of ferrocene complexes, mention of the high-spin 5(d-d) state is scarce. Here, we provide clear evidence of 5(d-d) formation in a bimetallic D-A molecule, ferrocenyl cobaltocenium hexafluorophosphate ([FcCc]PF6). Femtosecond optical transient absorption (OTA) spectroscopy reveals two distinct electronic excited states with 30 and 500 ps lifetimes. Using a combination of ultraviolet, visible, near-infrared, and short-wave infrared probe pulses, we capture the spectral features of these states over an ultrabroadband range spanning 320 to 2200 nm. Time-dependent density functional theory (DFT) calculations of the lowest triplet and quintet states, both primarily Fe(II) (d-d) in character, qualitatively agree with the experimental OTA spectra, allowing us to assign the 30 ps state as the 3(d-d) state and the 500 ps state as the high-spin 5(d-d) state. To confirm the ferrocene-centered high-spin character of the 500 ps state, we performed X-ray transient absorption (XTA) spectroscopy at the Fe and Co K edges. The Fe K-edge XTA spectrum at 150 ps shows a red shift of the absorption edge that is consistent with an Fe(II) high-spin state, as supported by ab initio calculations. The transient signal detected at the Co K-edge is 50× weaker, confirming the ferrocene-centered character of the excited state. Fitting of the transient extended X-ray absorption fine structure region yields an Fe-C bond length increase of 0.25 ± 0.1 Å in the excited state, as expected for the high-spin state based on DFT. Altogether, these results demonstrate that the high-spin state of ferrocene should be considered when designing donor-acceptor assemblies for photocatalysis and photovoltaics.
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Photoassisted catalysis using Ni complexes is an emerging field for cross-coupling reactions in organic synthesis. However, the mechanism by which light enables and enhances the reactivity of these complexes often remains elusive. Although optical techniques have been widely used to study the ground and excited states of photocatalysts, they lack the specificity to interrogate the electronic and structural changes at specific atoms. Herein, we report metal-specific studies using transient Ni L- and K-edge X-ray absorption spectroscopy of a prototypical Ni photocatalyst, (dtbbpy)Ni(o-tol)Cl (dtb = 4,4'-di-tert-butyl, bpy = bipyridine, o-tol = ortho-tolyl), in solution. We unambiguously confirm via direct experimental evidence that the long-lived (â¼5 ns) excited state is a tetrahedral metal-centered triplet state. These results demonstrate the power of ultrafast X-ray spectroscopies to unambiguously elucidate the nature of excited states in important transition-metal-based photocatalytic systems.
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X-ray absorption spectroscopy (XAS) is widely used across the life and physical sciences to identify the electronic properties and structure surrounding a specific element. XAS is less often used for the characterization of organometallic compounds, especially for sensitive and highly reactive species. In this study, we used solid- and solution-phase XAS to compare a series of 25 palladium complexes in controlled ligand environments. The compounds include palladium centers in the formal I, II, III, and IV oxidation states, supported by tridentate and tetradentate macrocyclic ligands, with different halide and methyl ligand combinations. The Pd K-edge energies increased not only upon oxidizing the metal center but also upon increasing the denticity of the ligand framework, substituting sigma-donating methyl groups with chlorides, and increasing the charge of the overall metal complex by replacing charged ligands with neutral ligands. These trends were then applied to characterize compounds whose oxidation states were otherwise unconfirmed.
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The broader utilization of 64Cu positron emission tomography (PET) imaging agents has been hindered by the unproductive demetalation induced by bioreductants. To advance the development of 64Cu-based PET imaging tracers for Alzheimer's Disease (AD), there is a need for novel ligand design strategies. In this study, we developed sulfur-containing dithiapyridinophane (N2S2) bifunctional chelators (BFCs) as well as all nitrogen-based diazapyridinophane (N4) BFCs to compare their abilities to chelate Cu and target Aß aggregates. Through spectrophotometric titrations and electrochemical measurements, we have demonstrated that the N2S2-based BFCs exhibit >10 orders of magnitude higher binding affinity toward Cu(I) compared to their N4-based counterparts, while both types of BFCs exhibit high stability constants toward Cu(II). Notably, solid state structures for both Cu(II) and Cu(I) complexes supported by the two ligand frameworks were obtained, providing molecular insights into their copper chelating abilities. Aß binding experiments were conducted to study the structure-affinity relationship, and fluorescence microscopy imaging studies confirmed the selective labeling of the BFCs and their copper complexes. Furthermore, we investigated the potential of these ligands for the 64Cu-based PET imaging of AD through radiolabeling and autoradiography studies. We believe our findings provide molecular insights into the design of bifunctional Cu chelators that can effectively stabilize both Cu(II) and Cu(I) and, thus, can have significant implications for the development of 64Cu PET imaging as a diagnostic tool for AD.
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Enfermedad de Alzheimer , Quelantes , Humanos , Quelantes/química , Enfermedad de Alzheimer/diagnóstico por imagen , Cobre , Radioisótopos de Cobre/química , Ligandos , Tomografía de Emisión de Positrones/métodosRESUMEN
Herein, we report the synthesis, characterization, and electrocatalytic CO2 reduction activity of a series of Pd(II) complexes supported by tetradentate pyridinophane ligands. In particular, we focus on the electrocatalytic CO2 reduction activity of a Pd(II) complex supported by the mixed hard--soft donor ligand 2,11-dithia[3.3](2,6)pyridinophane (N2S2). We also provide spectroscopic evidence of a CO-induced decomposition pathway for the same catalyst, which provides insights into catalyst poisoning for molecular Pd CO2 reduction electrocatalysts.
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Chromophores with zwitterionic excited-state intramolecular proton transfer (ESIPT) have been shown to have larger Stock shifts and red-shifted emission wavelengths compared to the conventional π-delocalized ESIPT molecules. However, there is still a dearth of design strategies to expand the current library of zwitterionic ESIPT compounds. Herein, a novel zwitterionic excited-state intramolecular proton transfer system is reported, enabled by addition of 1,4,7-triazacyclononane (TACN) fragments on a dicyanomethylene-4H-pyran (DCM) scaffold. The solvent-dependent steady-state photophysical studies, pKa measurements, and computational analysis strongly support that the ESIPT process is more efficient with two TACN groups attached to the DCM scaffold and not affected by polar protic solvents. Impressively, compound DCM-OH-2-DT exhibits a near-infrared (NIR) emission at 740â nm along with an uncommonly large Stokes shift. Moreover, DCM-OH-2-DT shows high affinity towards soluble amyloid ß (Aß) oligomers inâ vitro and in 5xFAD mouse brain sections, and we have successfully applied DCM-OH-2-DT for the inâ vivo imaging of Aß aggregates and demonstrated its potential use as an early diagnostic agent for AD. Overall, this study can provide a general molecular design strategy for developing new zwitterionic ESIPT compounds with NIR emission inâ vivo imaging applications.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Animales , Ratones , Protones , Enfermedad de Alzheimer/diagnóstico por imagen , SolventesRESUMEN
Nickel K- and L2,3-edge X-ray absorption spectra (XAS) are discussed for 16 complexes and complex ions with nickel centers spanning a range of formal oxidation states from II to IV. K-edge XAS alone is shown to be an ambiguous metric of physical oxidation state for these Ni complexes. Meanwhile, L2,3-edge XAS reveals that the physical d-counts of the formally NiIV compounds measured lie well above the d6 count implied by the oxidation state formalism. The generality of this phenomenon is explored computationally by scrutinizing 8 additional complexes. The extreme case of NiF62- is considered using high-level molecular orbital approaches as well as advanced valence bond methods. The emergent electronic structure picture reveals that even highly electronegative F-donors are incapable of supporting a physical d6 NiIV center. The reactivity of NiIV complexes is then discussed, highlighting the dominant role of the ligands in this chemistry over that of the metal centers.
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Described herein is the synthesis of the NiII complex (tBuMe2tacn)NiII(cycloneophyl) (tBuMe2tacn = 1-tert-butyl-4,7-dimethyl-1,4,7-triazacyclononane, cycloneophyl = -CH2CMe2-o-C6H4-) and its reactivity with dioxygen and peroxides. The new tBuMe2tacn ligand is designed to enhance the oxidatively induced bond-forming reactivity of high-valent Ni intermediates. Tunable chemoselectivity for Csp2-O vs Csp2-Csp3 bond formation was achieved by selecting the appropriate solvent and reaction conditions. Importantly, the use of cumene hydroperoxide and meta-chloroperbenzoic acid suggests a heterolytic O-O bond cleavage upon reaction with (tBuMe2tacn)NiII(cycloneophyl). Mechanistic studies using isotopically labeled H2O2 support the generation of a high-valent Ni-oxygen species via an inner-sphere mechanism and subsequent reductive elimination to form the Csp2-O bond. Kinetic studies of the exceptionally fast Csp2-O bond-forming reaction reveal a first-order dependence on both (tBuMe2tacn)NiII(cycloneophyl) and H2O2, and thus an overall second-order reaction. Eyring analysis further suggests that the oxidation of the NiII complex by H2O2 is the rate-determining step, which can be modulated by the presence of coordinating solvents. Moreover, computational studies fully support the conclusions drawn from experimental results. Overall, this study reveals for the first time the ability to control the oxidatively induced C-C vs C-O bond formation reactions at a Ni center. Importantly, the described system merges the known organometallic reactivity of Ni with the biomimetic oxidative transformations resembling oxygenases and peroxidases, and involving high-valent metal-oxygen intermediates, which is a novel approach that should lead to unprecedented oxidative catalytic transformations.
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Herein we report the direct observation of C-H bond activation at an isolated mononuclear Pd(iii) center. The oxidation of the Pd(ii) complex (MeN4)PdII(neophyl)Cl (neophyl = -CH2C(CH3)2Ph; MeN4 = N,N'-dimethyl-2,11-diaza[3.3](2,6)pyridinophane) using the mild oxidant ferrocenium hexafluorophosphate (FcPF6) yields the stable Pd(iii) complex [(MeN4)PdIII(neophyl)Cl]PF6. Upon the addition of an acetate source, [(MeN4)PdIII(neophyl)Cl]PF6 undergoes Csp2-H bond activation to yield the cyclometalated product [(MeN4)PdIII(cycloneophyl)]PF6. This metalacycle can be independently prepared, allowing for a complete characterization of both the starting and final Pd(iii) complexes. The C-H activation step can be monitored directly by EPR and UV-Vis spectroscopies, and kinetic isotope effect (KIE) studies suggest that either a pre-association step such as an agostic interaction may be rate limiting, or that the C-H activation is partially rate-limiting in conjunction with ligand rearrangement. Density functional theory calculations support that the reaction proceeds through a κ3 ligand coordination and that the flexible ligand structure is important for this transformation. Overall, this study represents the first example of discrete C-H bond activation occurring at a Pd(iii) center through a concerted metalation-deprotonation mechanism, akin to that observed for Pd(ii) and Pd(iv) centers.
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Visualizing redox-active metal ions, such as Fe2+ and Fe3+ ions, are essential for understanding their roles in biological processes and human diseases. Despite the development of imaging probes and techniques, imaging both Fe2+ and Fe3+ simultaneously in living cells with high selectivity and sensitivity has not been reported. Here, we selected and developed DNAzyme-based fluorescent turn-on sensors that are selective for either Fe2+ or Fe3+, revealing a decreased Fe3+/Fe2+ ratio during ferroptosis and an increased Fe3+/Fe2+ ratio in Alzheimer's disease mouse brain. The elevated Fe3+/Fe2+ ratio was mainly observed in amyloid plaque regions, suggesting a correlation between amyloid plaques and the accumulation of Fe3+ and/or conversion of Fe2+ to Fe3+. Our sensors can provide deep insights into the biological roles of labile iron redox cycling.
Asunto(s)
Enfermedad de Alzheimer , Ratones , Animales , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Hierro , Metales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Placa Amiloide , Péptidos beta-Amiloides/metabolismoRESUMEN
Significant progress has been made in the bioinorganic modeling of the paramagnetic states believed to be involved in the hydrogen redox chemistry catalyzed by [NiFe] hydrogenase. However, the characterization and isolation of intermediates involved in mononuclear Ni electrocatalysts which are reported to operate through a NiI/III cycle have largely remained elusive. Herein, we report a NiII complex (NCHS2)Ni(OTf)2, where NCHS2 is 3,7-dithia-1(2,6)-pyridina-5(1,3)-benzenacyclooctaphane, that is an efficient electrocatalyst for the hydrogen evolution reaction (HER) with turnover frequencies of ~3,000 s-1 and a overpotential of 670 mV in the presence of trifluoroacetic acid. This electrocatalyst follows a hitherto unobserved HER mechanism involving C-H activation, which manifests as an inverse kinetic isotope effect for the overall hydrogen evolution reaction, and NiI/NiIII intermediates, which have been characterized by EPR spectroscopy. We further validate the possibility of the involvement of NiIII intermediates by the independent synthesis and characterization of organometallic NiIII complexes.
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The misfolded proteins or polypeptides commonly observed in neurodegenerative diseases, including Alzheimer's disease (AD), are promising drug targets for developing therapeutic agents. To target the amyloid-ß (Aß) peptide plaques and oligomers, the hallmarks of AD, we have developed twelve amphiphilic small molecules with different hydrophobic and hydrophilic fragments. In vitro fluorescence binding assays demonstrate that these amphiphilic compounds show high binding affinity to both Aß plaques and oligomers, and six of them exhibit selective binding toward Aß oligomers. These amphiphilic compounds can also label the Aß species in the brain sections of transgenic AD mice, as shown by immunostaining with an Aß antibody. Molecular docking studies were performed to obtain structure-affinity relationships. To our delight, four amphiphilic compounds can alleviate the Cu2+-Aß induced toxicity in cell viability assays. In addition, confocal fluorescence imaging studies provide evidence that two compounds, ZY-15-MT and ZY-15-OMe, can disrupt the interactions between Aß oligomers and human neuroblastoma SH-SY5Y cell membranes. Overall, these studies strongly suggest that developing compounds with amphiphilic properties that target Aß oligomers and modulate the Aß oligomer-cell membrane interactions can be an effective strategy for the development of small molecule AD therapeutics.
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Herein, we report a new series of divalent 2-(4-hydroxyphenyl)benzothiazole bifunctional chelators (BFCs) with high affinity for amyloid ß aggregates and favorable lipophilicity for blood-brain barrier penetration. The addition of an alkyl carboxylate ester pendant arm offers high binding affinity toward Cu(II). The novel BFCs form stable 64Cu-radiolabeled complexes and exhibit promising partition coefficient (logD) values of 1.05-1.85. Among the five compounds tested, the 64Cu-YW-15 complex exhibits significant staining of amyloid ß plaques in ex vivo autoradiography studies. In addition, biodistribution studies show that 64Cu-YW-15-Me exhibits moderate brain uptake (0.69 ± 0.08 %ID/g) in wild type mice.
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Enfermedad de Alzheimer , Quelantes , Tomografía de Emisión de Positrones , Animales , Ratones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/química , Benzotiazoles/química , Benzotiazoles/farmacocinética , Quelantes/química , Placa Amiloide/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Distribución TisularRESUMEN
Catalytic transformations involving Pd(0)/Pd(II) catalytic cycles are very well known, and processes involving high-valent Pd(III) and Pd(IV) and low-valent Pd(I) intermediates have also gained interest in recent years. Although low-valent Pd(I) intermediates are proposed in these catalytic cycles, isolated and characterized mononuclear Pd(I) species are very rare. Herein, we report the isolation of two heteroleptic mononuclear Pd(I) complexes stabilized by dithiapyridinophane ligands that were fully characterized by single-crystal X-ray diffraction; EPR, IR, UV-vis spectroscopies; and computational studies. Excitingly, one of these Pd(I) complexes shows Kumada Csp3-Csp2 cross-coupling competency, and initial studies of the other shows direct evidence for Csp3-H bond activation proposed to occur at the Pd(I) center.
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Paladio , Paladio/química , Catálisis , LigandosRESUMEN
Protein misfolding and metal dishomeostasis are two key pathological factors of Alzheimer's disease. Previous studies have shown that Cu-mediated amyloid ß (Aß) peptide aggregation leads to the formation of neurotoxic Aß oligomers. Herein, we report a series of picolinic acid-based Cu-activatable sensors, which can be used for the fluorescence imaging of Cu-rich Aß aggregates.
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An isolated Ni(II)-nitrosyl complex supported by the bulky tridentate 1,4,7-triisopropyl-1,4,7-triazacyclononane (iPr3TACN) ligand was obtained from the reaction of a Ni(II) dimethyl complex with NOPF6, suggesting the in situ formation of a Ni(I) species that reacts with the resulting NO product. Use of a π-acceptor ancillary isocyanide ligand led to the isolation and characterization of an uncommon 5-coordinate Ni(I) complex supported by the iPr3TACN ligand and tert-butylisocyanide.
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Níquel , Compuestos Organometálicos , Compuestos Heterocíclicos , Ligandos , Modelos Moleculares , Estructura MolecularRESUMEN
Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with progressive neuronal cell death, and they are commonly correlated with aberrant protein misfolding and aggregation of Aß peptides. Transition metal ions (Cu, Fe, and Zn) have been shown to promote aggregation and oxidative stress through formation of Aß-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two azo-stilbene (AS)-derived compounds (AS-HL1 and AS-HL2), the rationale behind the design, their synthesis, characterization, and metal chelation ability [Cu(II) and Zn(II)]. The molecular frameworks of the designed compounds consist of stilbene as an Aß-interacting moiety, whereas N,N,O and N,N,N,O donor atoms are linked to generate the metal chelation moiety. Furthermore, we went on exploring their multifunctionality with respect to (w.r.t.) (i) their metal chelating capacities and (ii) their utility to modulate the aggregation pathways of both metal-free and metal-bound amyloid-ß, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase and (v) cytotoxicity. Moreover, the compounds were able to sequester Cu2+ from the Aß-Cu complex as studied by the UV-visible spectroscopic assay. Molecular docking studies were also performed with Aß and acetylcholinesterase enzyme. Overall, the studies presented here qualify these molecules as promising candidates for further investigation in the quest for finding a treatment for Alzheimer's disease.
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Enfermedad de Alzheimer , Estilbenos , Acetilcolinesterasa , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Aminas , Péptidos beta-Amiloides/química , Quelantes/química , Cobre/química , Humanos , Metales , Simulación del Acoplamiento Molecular , Piridinas , Estilbenos/farmacologíaRESUMEN
A recent theranostic approach to address Alzheimer's disease (AD) utilizes multifunctional targets that both tag and negate the toxicity of AD biomarkers. These compounds, which emit fluorescence with both an activation and a spectral shift in the presence of Aß, were previously characterized with traditional fluorescence imaging for binary characterization. However, these multifunctional compounds have broad and dynamic emission spectra that are dependent on factors such as the local environment, presence of Aß deposits, etc. Since quantitative multiphoton microscopy is sensitive to the binding dynamics of molecules, we characterized the performance of two such compounds, LS-4 and ZY-12-OMe, using Simultaneous Label-free Autofluorescence Multi-harmonic (SLAM) microscopy and Fast Optical Coherence, Autofluorescence Lifetime imaging and Second harmonic generation (FOCALS) microscopy. This study shows that the combination of quantitative multiphoton imaging with multifunctional tags for AD offers new insights into the interaction of these tags with AD biomarkers and the theranostic mechanisms.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico por imagen , Biomarcadores , Colorantes , Humanos , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Imagen ÓpticaRESUMEN
Timely diagnostic imaging plays a crucial role in managing cerebral amyloid angiopathy (CAA)-the condition in which amyloid ß is deposited on blood vessels. To selectively map these amyloid plaques, we have designed amyloid-targeting ligands that can effectively complex with 68Ga3+ while maintaining good affinity for amyloid ß. In this study, we introduced novel 1,4,7-triazacyclononane-based bifunctional chelators (BFCs) that incorporate a benzothiazole moiety as the Aß-binding fragment and form charged and neutral species with 68Ga3+. In vitro autoradiography using 5xFAD and WT mouse brain sections (11-month-old) suggested strong and specific binding of the 68Ga complexes to amyloid ß. Biodistribution studies in CD-1 mice revealed a low brain uptake of 0.10-0.33% ID/g, thus suggesting 68Ga-labeled novel BFCs as promising candidates for detecting CAA.