Ultrasmall Mn-doped iron oxide nanoparticles with dual hepatobiliary and renal clearances for T1 MR liver imaging.

Although magnetic nanoparticles demonstrate significant potential as magnetic resonance imaging (MRI) contrast agents, their negative contrasts, liver accumulation, and limited excretion hinder their application. Herein, we developed ultrasmall Mn-doped iron oxide nanoparticles (UMIOs) with distinct advantages as T1 MRI contrast agents. Exceptionally small particle sizes (ca. 2 nm) and magnetization values (5 emu gMn+Fe-1) of UMIOs provided optimal T1 contrast effects with an ideally low r2/r1 value of ∼1. Furthermore, the use of Mn as a dopant facilitated hepatocyte uptake of the particles, allowing liver imaging. In animal studies, UMIOs exhibited significantly enhanced contrasts for sequential T1 imaging of blood vessels and the liver, distinguishing them from conventional magnetic nanoparticles. UMIOs were systematically cleared via dual hepatobiliary and renal excretion pathways, highlighting their safety profile. These characteristics imply substantial potential of UMIOs as T1 contrast agents for the accurate diagnosis of liver diseases.

Mechanistic snapshots of rhodium-catalyzed acylnitrene transfer reactions.

Rhodium (Rh) acylnitrene complexes are widely implicated in catalytic C-H amidation reactions but have eluded isolation and structural characterization. To overcome this challenge, we designed a chromophoric octahedral Rh complex with a bidentate dioxazolone ligand, in which photoinduced metal-to-ligand charge transfer initiates catalytic C-H amidation. X-ray photocrystallographic analysis of the Rh-dioxazolone complex allowed structural elucidation of the targeted Rh-acylnitrenoid and provided firm evidence that the singlet nitrenoid species is primarily responsible for acylamino transfer reactions. We also monitored in crystallo reaction of a nucleophile with the in situ-generated Rh-acylnitrenoid, which provided a crystallographically traceable reaction system to capture mechanistic snapshots of nitrenoid transfer.

Copper(II) and zinc(II) complexation with N-ethylene hydroxycyclams and consequences on the macrocyclic backbone configuration.

We report a series of four cyclams and cross-bridged cyclams, N-functionalized by one hydroxyethyl arm, which may incorporate additional methyl(s) group(s). The Cu(II) and Zn(II) complexes of these ligands were synthesized and fully characterized. The investigation of the metal complexes in solid-state and in solution was carried via X-ray diffraction, NMR, EPR, absorption spectroscopy and DFT calculations. The influence of N-functionalization on their structural/stereochemical properties, electrochemical behavior and kinetic inertness was carefully studied and identified. N-Functionalization by a hydroxyethyl group did not influence importantly the stereochemical properties of the complexes. However, it stabilized the complexes kinetically and electrochemically. As for N-methylation, it induces significant distortion of the coordination geometry, decreasing the kinetic inertness of the complexes and stabilizing Cu+. Overall, this work expanded the family of cyclam and cross-bridged cyclam metal complexes and provides a detailed analysis of their structural features. The rather large body of data accumulated for this family of complexes provides opportunities to design systems with pre-determined properties for specific applications.

Circularly Polarized Light Can Override and Amplify Asymmetry in Supramolecular Helices.

Circularly polarized light (CPL) is an inherently chiral entity and is considered one of the possible deterministic signals that led to the evolution of homochirality. While accumulating examples indicate that chirality beyond the molecular level can be induced by CPL, not much is yet known about circumstances where the spin angular momentum of light competes with existing molecular chiral information during the chirality induction and amplification processes. Here we present a light-triggered supramolecular polymerization system where chiral information can both be transmitted and nonlinearly amplified in a "sergeants-and-soldiers" manner. While matching handedness with CPL resulted in further amplification, we determined that opposite handedness could override molecular information at the supramolecular level when the enantiomeric excess was low. The presence of a critical chiral bias suggests a bifurcation point in the homochirality evolution under random external chiral perturbation. Our results also highlight opportunities for the orthogonal control of supramolecular chirality decoupled from molecular chirality preexisting in the system.

Drug repurposing: small molecules against Cu(II)-amyloid-ß and free radicals.

Alzheimer's disease (AD) presents a complex pathology entangling numerous pathological factors, including amyloid-ß (Aß), metal ions, and reactive oxygen species (ROS). Increasing evidence reveals pathological connections among these distinct components in AD. For instance, the association between the amyloid cascade and metal ion hypotheses has introduced a novel pathogenic target: metal-bound Aß. Investigation of such interconnections requires substantial research and can be expedited by chemical reagents that are able to modify multiple pathogenic factors in AD. Drug repurposing is an efficient approach for rediscovering previously utilized molecules with desirable biological and pharmaceutical properties as chemical reagents. Herein, we report the evaluation of three pre-approved drug molecules, selected based on their chemical structure and properties, as chemical reagents that can be used for elucidating the complicated pathology of AD.

Complexation of C-Functionalized Cyclams with Copper(II) and Zinc(II): Similarities and Changes When Compared to Parent Cyclam Analogues.

Herein, we report a comprehensive coordination study of the previously reported ligands cyclam, CB-cyclam, TMC, DMC, and CB-DMC and of their C-functional analogues, cyclam-E, CB-cyclam-E, TMC-E, DMC-E, and CB-DMC-E. This group of ligands includes cyclam, cross-bridged cyclams, their di- or tetramethylated derivatives, and the analogues bearing an additional hydroxyethyl group on one ß-N position of the ring. The Cu(II) and Zn(II) complexes of these macrocycles have been highlighted previously for the biological interest, but the details of their structures in the solid state and in solution remained largely unexplored. In particular, we analyzed the impact that adding noncoordinating N-methyl and C-hydroxyethyl functionalities has in the structures of the complexes. All the Cu(II) and Zn(II) complexes were synthesized and investigated using single crystal X-ray diffraction and NMR, electronic absorption, and EPR spectroscopies, along with DFT studies. Dissociation kinetics experiments in acidic conditions and electrochemical studies were also performed. Special attention was paid to analyze the different configurations present in solution and in the solid state, as well as the impact of the C-appended hydroxyethyl group on the coordination behavior. Various ratios of the trans-I, trans-III, and cis-V configurations have been observed depending on the degree of N-methylation and the presence of the ethylene cross-bridge.

Ligand-field transition-induced C-S bond formation from nickelacycles.

Photoexcitation is one of the acknowledged methods to activate Ni-based cross-coupling reactions, but factors that govern the photoactivity of organonickel complexes have not yet been established. Here we report the excited-state cross-coupling activities of Ni(ii) metallacycle compounds, which display ∼104 times enhancement for the C-S bond-forming reductive elimination reaction upon Ni-centered ligand-field transitions. The effects of excitation energy and ancillary ligands on photoactivity have been investigated with 17 different nickelacycle species in combination with four corresponding acyclic complexes. Spectroscopic and computational electronic structural characterizations reveal that, regardless of coordinated species, d-d transitions can induce Ni-C bond homolysis, and that the reactivity of the resulting Ni(i) species determines the products of the overall reaction. The photoactivity mechanism established in this study provides general insights into the excited-state chemistry of organonickel(ii) complexes.

Sequential Connection of Mutually Exclusive Catalytic Reactions by a Method Controlling the Presence of an MOF Catalyst: One-Pot Oxidation of Alcohols to Carboxylic Acids.

A functionalized metal-organic framework (MOF) catalyst applied to the sequential one-pot oxidation of alcohols to carboxylic acids controls the presence of a heterogeneous catalyst. The conversion of alcohols to aldehydes was acquired through aerobic oxidation using a well-known amino-oxy radical-functionalized MOF. In the same flask, a simple filtration of the radical MOF with mild heating of the solution completely altered the reaction media, providing radical scavenger-free conditions suitable for the autoxidation of the aldehydes formed in the first step to carboxylic acids. The mutually exclusive radical-catalyzed aerobic oxidation (the first step with MOF) and radical-inhibited autoxidation (the second step without MOF) are sequentially achieved in a one-pot manner. Overall, we demonstrate a powerful and efficient method for the sequential oxidation of alcohols to carboxylic acids by employing a readily functionalizable heterogeneous MOF. In addition, our MOF in-and-out method can be utilized in an environmentally friendly way for the oxidation of alcohols to carboxylic acids of industrial and economic value with broad functional group tolerance, including 2,5-furandicarboxylic acid and 1,4-benzenedicarboxylic acid, with good yield and reusability. Furthermore, MOF-TEMPO, as an antioxidative stabilizer, prevents the undesired oxidation of aldehydes, and the perfect "recoverability" of such a reactive MOF requires a re-evaluation of the advantages of MOFs from heterogeneity in catalytic and related applications.

Mechanistic insight into hydroxamate transfer reaction mimicking the inhibition of zinc-containing enzymes.

A hydroxamate transfer reaction between metal complexes has been investigated by a combination of experimental and theoretical studies. A hydroxamate-bound cobalt(ii) complex bearing a tetradentate macrocyclic ligand, [CoII(TBDAP)(CH3C(-NHO)O)]+ (1), is prepared by the reduction of a hydroximatocobalt(iii) complex with a biological reductant. Alternatively, 1 is accessible via a synthetic route for the reaction between the cobalt(ii) complex and acetohydroxamic acid in the presence of a base. 1 was isolated and characterized by various physicochemical methods, including UV-vis, IR, ESI-MS, and X-ray crystallography. The hydroxamate transfer reactivity of 1 was examined with a zinc complex, which was followed by UV-vis and ESI-MS. Kinetic and activation parameter data suggest that the hydroxamate transfer reaction occurs via a bimolecular mechanism, which is also supported by DFT calculations. Moreover, 1 is able to inhibit the activity against a zinc enzyme, i.e., matrix metalloproteinase-9. Our overall investigations of the hydroxamate transfer using the synthetic model system provide considerable insight into the final step involved in the inhibition of zinc-containing enzymes.

Strategies Employing Transition Metal Complexes To Modulate Amyloid-ß Aggregation.

Aggregation of amyloid-ß (Aß) peptides is implicated in the development of Alzheimer's disease (AD), the most common type of dementia. Thus, numerous efforts to identify chemical tactics to control the aggregation pathways of Aß peptides have been made. Among them, transition metal complexes as a class of chemical modulators against Aß aggregation have been designed and utilized. Transition metal complexes are able to carry out a variety of chemistry with Aß peptides (e.g., coordination chemistry and oxidative and proteolytic reactions for peptide modifications) based on their tunable characteristics, including the oxidation state of and coordination geometry around the metal center. This Viewpoint illustrates three strategies employing transition metal complexes toward modulation of Aß aggregation pathways (i.e., oxidation and hydrolysis of Aß as well as coordination to Aß), along with some examples of such transition metal complexes. In addition, proposed mechanisms for three reactivities of transition metal complexes with Aß peptides are discussed. Our greater understanding of how transition metal complexes have been engineered and used for alteration of Aß aggregation could provide insight into the new discovery of chemical reagents against Aß peptides found in AD.

Tuning Structures and Properties for Developing Novel Chemical Tools toward Distinct Pathogenic Elements in Alzheimer's Disease.

Multiple pathogenic factors [e.g., amyloid-ß (Aß), metal ions, metal-bound Aß (metal-Aß), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer's disease (AD). In order to elucidate the roles of pathological elements in AD, chemical tools able to regulate their activities would be valuable. Due to the complicated link among multiple pathological factors, however, it has been challenging to invent such chemical tools. Herein, we report novel small molecules as chemical tools toward modulation of single or multiple target(s), designed via a rational structure-property-directed strategy. The chemical properties (e.g., oxidation potentials) of our molecules and their coverage of reactivities toward the pathological targets were successfully differentiated through a minor structural variation [i.e., replacement of one nitrogen (N) or sulfur (S) donor atom in the framework]. Among our compounds (1-3), 1 with the lowest oxidation potential is able to noticeably modify the aggregation of both metal-free Aß and metal-Aß, as well as scavenge free radicals. Compound 2 with the moderate oxidation potential significantly alters the aggregation of Cu(II)-Aß42. The hardly oxidizable compound, 3, relative to 1 and 2, indicates no noticeable interactions with all pathogenic factors, including metal-free Aß, metal-Aß, and free radicals. Overall, our studies demonstrate that the design of small molecules as chemical tools able to control distinct pathological components could be achieved via fine-tuning of structures and properties.

Link of impaired metal ion homeostasis to mitochondrial dysfunction in neurons.

Manganese, iron, copper, and zinc are observed to play essential roles in mitochondria. The overload and depletion of metal ions in mitochondria under pathological conditions, however, could disturb mitochondrial compartments and functions leading to cell death. In this review, we mainly summarize how impaired metal ion homeostasis affects mitochondrial systems, such as membrane potentials, the tricarboxylic acid cycle, oxidative phosphorylation, and glutathione metabolism. In addition, based on current findings, we briefly describe a recent understanding of the relationship among metal ion dysregulation, mitochondrial dysfunction, and the pathogeneses of neurodegenerative diseases.

Minor Structural Variations of Small Molecules Tune Regulatory Activities toward Pathological Factors in Alzheimer's Disease.

Chemical tools have been valuable for establishing a better understanding of the relationships between metal ion dyshomeostasis, the abnormal aggregation and accumulation of amyloid-ß (Aß), and oxidative stress in Alzheimer's disease (AD). Still, very little information is available to correlate the structures of chemical tools with specific reactivities used to uncover such relationships. Recently, slight structural variations to the framework of a chemical tool were found to drastically determine the tool's reactivities toward multiple pathological facets to various extents. Herein, we report our rational design and characterization of a structural series to illustrate the extent to which the reactivities of small molecules vary toward different targets as a result of minor structural modifications. These compounds were rationally and systematically modified based on consideration of properties, including ionization potentials and metal binding, to afford their desired reactivities with metal-free or metal-bound Aß, reactive oxygen species (ROS), and free organic radicals. Our results show that although small molecules are structurally similar, they can interact with multiple factors associated with AD pathogenesis and alleviate their reactivities to different degrees. Together, our studies demonstrate the rational structure-directed design that can be used to develop chemical tools capable of regulating individual or interrelated pathological features in AD.