Synthetic Advances for Mechanistic Insights: Metal-Oxygen Intermediates with a Macrocyclic Pyridinophane System.

ConspectusMetalloenzymes, which are proteins containing earth-abundant transition-metal ions as cofactors in the active site, generate various metal-oxygen intermediates via activating a dioxygen molecule (O2) to mediate vital metabolic functions, such as the oxidative metabolism of xenobiotics and the biotransformation of naturally occurring molecules. By replicating the active sites of metalloenzymes, many bioinorganic chemists have studied the geometric and electronic properties and reactivities of model complexes to understand the nature of enzymatic intermediates and develop bioinspired metal catalysts. Among the reported model complexes, nonporphyrinic macrocyclic ligands are the predominant coordination system widely used in stabilizing and isolating diverse metal-oxygen intermediates, which allows us to extensively investigate the physicochemical characteristics of the analogs of reactive intermediates of metalloenzymes. In particular, it has been reported that the ring size of the macrocyclic ligands, defined by the number of atoms in the macrocyclic ring, drastically affects the identity of the metal-oxygen intermediate. Thus, systematic modification of the macrocyclic ligands has been a great subject being examined in various inorganic fields.In this Account, we describe synthetic advances of a macrocyclic ligand system by introducing pyridine donors into a 12-membered tetraazamacrocyclic ligand (12-TMC) that initially has 4 amine donors. Interestingly, the backbone of the pyridinophane ligand with 2 pyridine and 2 amine donors in a 12-membered ring is shown to be much more folded than in other macrocyclic ligands, thereby allowing the axial and equatorial donors to separately control the electronic structure of metal complexes. Then, we looked over independent electronic and steric effects on metal-oxygen species with thorough physicochemical analysis. The NiIII-peroxo complexes exhibit nucleophilic reactivity dependent on the steric hindrance of the second coordination sphere. Furthermore, the C-H bond strength of the second coordination sphere has also been an important factor in determining the stability of MnIV-bis(hydroxo) intermediates. Electronic tuning on CoIII-hydroperoxo intermediates results in a trend between the electron-donating abilities of para-substituents on pyridine in the pyridinophane ligand and electrophilic reactivities, from which mechanistic insights into the metal-hydroperoxo species have been gained. Importantly, the metal-oxygen intermediates supported by the pyridinophane ligand system have revealed quite challenging chemical reactions, including dioxygenase-like nitrile activation by CoIII-peroxo intermediates and the oxidation of aldehyde and aromatic compounds by manganese-oxygen intermediates. Based on the fine substitution of donors, we have addressed that those novel reactions originated from the unique framework of the pyridinophane system incorporating spin-crossover behavior and high redox potentials of the metal-oxygen intermediates. These results will be valuable for the structure-activity relationship of metal-oxygen intermediates, giving a better understanding on the enzymatic coordination system where amino acid ligands vary for specific chemical reactions.

Synthesis, Characterization, and Reactivity of a Highly Oxidative Mononuclear Manganese(IV)-Bis(Fluoro) Complex.

Recently, transition-metal terminal nonoxo complexes have shown a remarkable ability to activate and functionalize C-H bonds via proton-coupled electron transfer (PCET). Here we report the first example of a mononuclear manganese(IV) bis(fluoro) complex bearing a tetradentate pyridinophane ligand, [MnIV(TBDAP)(F)2]2+ (3), with an X-ray single crystal structure and physicochemical characterization. The manganese(IV) bis(fluoro) complex has a very high reduction potential of 1.61 V vs SCE, thereby enabling the four-electron oxidation of mesitylene to 3,5-dimethylbenzaldehyde. Kinetic studies, including the kinetic isotope effect and employment of other toluene derivatives, reveal the electron transfer (ET)-driven PCET in the C-H bond activation of mesitylene by 3. This novel metal halide intermediate would be prominently valuable for expanding transition-metal halide chemistry.

Aliphatic and Aromatic C-H Bond Oxidation by High-Valent Manganese(IV)-Hydroxo Species.

The strong C-H bond activation of hydrocarbons is a difficult reaction in environmental and biological chemistry. Herein, a high-valent manganese(IV)-hydroxo complex, [MnIV(CHDAP-O)(OH)]2+ (2), was synthesized and characterized by various physicochemical measurements, such as ultraviolet-visible (UV-vis), electrospray ionization-mass spectrometry (ESI-MS), electron paramagnetic resonance (EPR), and helium-tagging infrared photodissociation (IRPD) methods. The one-electron reduction potential (Ered) of 2 was determined to be 0.93 V vs SCE by redox titration. 2 is formed via a transient green species assigned to a manganese(IV)-bis(hydroxo) complex, [MnIV(CHDAP)(OH)2]2+ (2'), which performs intramolecular aliphatic C-H bond activation. The kinetic isotope effect (KIE) value of 4.8 in the intramolecular oxidation was observed, which indicates that the C-H bond activation occurs via rate-determining hydrogen atom abstraction. Further, complex 2 can activate the C-H bonds of aromatic compounds, anthracene and its derivatives, under mild conditions. The KIE value of 1.0 was obtained in the oxidation of anthracene. The rate constant (ket) of electron transfer (ET) from N,N'-dimethylaniline derivatives to 2 is fitted by Marcus theory of electron transfer to afford the reorganization energy of ET (λ = 1.59 eV). The driving force dependence of log ket for oxidation of anthracene derivatives by 2 is well evaluated by Marcus theory of electron transfer. Detailed kinetic studies, including the KIE value and Marcus theory of outer-sphere electron transfer, imply that the mechanism of aromatic C-H bond hydroxylation by 2 proceeds via the rate-determining electron-transfer pathway.

Antioxidant Analogue 6-Amino-2,4,5-Trimethylpyridin-3-ol Ameliorates Experimental Colitis in Mice.

BACKGROUND: Oxidative stress has been suggested to be a factor contributing to the disease severity of inflammatory bowel disease (IBD). BJ-1108, a derivative of 6-amino-2,4,5-trimethylpyridin-3-ol, is reported to significantly inhibit the generation of reactive oxygen species (ROS) in vitro. However, whether this molecule affects intestinal inflammation is largely unknown. We aimed to investigate the effect of BJ-1108 on dextran sulfate sodium (DSS)-induced experimental colitis in mice. METHODS: Colitis was induced in mice with DSS, and disease severity was estimated by evaluating body weight, colon length, histology, immune cell infiltration, and intestinal permeability. We examined the protective effects of BJ-1108 on barrier function using Caco-2 cells. Last, we estimated the impact of BJ-1108 on the phosphorylation of NF-kB, PI3K/AKT, and mitogen-activated protein kinases. RESULTS: Mice treated with BJ-1108 exhibited improved disease severity, as indicated by evaluations of body weight, histological scores, spleen weight, and infiltrates of T cells and macrophages. The administration of BJ-1108 inhibited the colonic mRNA expression of IL-6 and IL-1ß in vivo. Additionally, BJ-1108 limited intestinal permeability and enhanced the expression of tight junction (TJ) proteins such as claudin-1 and claudin-3 in the DSS-induced colitis model. In an in vitro model using Caco-2 cells, BJ-1108 ameliorated cytokine-induced ROS generation in a dose-dependent manner and remarkably recovered barrier dysfunction as estimated by evaluating transepithelial electrical resistance and TJ protein expression. BJ-1108 suppressed the NF-kB/ERK/PI3K pathway. CONCLUSIONS: This study demonstrated that BJ-1108 ameliorated intestinal inflammation in an experimental colitis mouse model, suggesting possible therapeutic implications for IBD.

Metal Nanoparticle Exsolution on a Perovskite Stannate Support with High Electrical Conductivity.

In situ exsolution of metal nanoparticles (NPs) is emerging as an alternative technique to deliver thermally stable and evenly dispersed metal NPs, which exhibit excellent adhesion with conducting perovskite oxide supports. Here we provide the first demonstration that Ni metal NPs with high areal density (∼175 µm-2) and fine size (∼38.65 nm) are exsolved from an A-site-deficient perovskite stannate support (La0.2Ba0.7Sn0.9Ni0.1O3-δ (LBSNO)). The NPs are strongly anchored and impart coking resistance, and the Ni-exsolved stannates show exceptionally high electrical conductivity (∼700 S·cm-1). The excellent conductivity is attributed to conduction between delocalized Sn 5s orbitals along with structural improvement toward ABO3 stoichiometry in the stannate support. We also reveal that experimental conditions with strong interaction must be optimized to obtain Ni exsolution without degrading the perovskite stannate framework. Our finding suggests a unique process to induce the formation of metal NPs embedded in stannate with excellent electrical properties.

Transmission Electron Microscopy Confirmation of Orientia tsutsugamushi in Human Bile.

Scrub typhus, the third most frequently reported infectious disease in South Korea, causes serious public health problems. In 2019, we collected a bile specimen from a patient with scrub typhus through percutaneous transhepatic gallbladder drainage and performed transmission electron microscopy to confirm the ultrastructure of Orientia tsutsugamushi.

Epitaxially Grown Ferroelectric PVDF-TrFE Film on Shape-Tailored Semiconducting Rubrene Single Crystal.

Epitaxial crystallization of thin poly(vinylidene fluoride-co-trifluoroethylene) (PVDF-TrFE) films is important for the full utilization of their ferroelectric properties. Epitaxy can offer a route for maximizing the degree of crystallinity with the effective orientation of the crystals with respect to the electric field. Despite various approaches for the epitaxial control of the crystalline structure of PVDF-TrFE, its epitaxy on a semiconductor is yet to be accomplished. Herein, the epitaxial growth of PVDF-TrFE crystals on a single-crystalline organic semiconductor rubrene grown via physical vapor deposition is presented. The epitaxy results in polymer crystals globally ordered with specific crystal orientations dictated by the epitaxial relation between the polymer and rubrene crystal. The lattice matching between the c-axis of PVDF-TrFE crystals and the (210) plane of orthorhombic rubrene crystals develops two degenerate crystal orientations of the PVDF-TrFE crystalline lamellae aligned nearly perpendicular to each other. Thin PVDF-TrFE films with epitaxially grown crystals are incorporated into metal/ferroelectric polymer/metal and metal/ferroelectric polymer/semiconductor/metal capacitors, which exhibit excellent nonvolatile polarization and capacitance behavior, respectively. Furthermore, combined with a printing technique for micropatterning rubrene single crystals, the epitaxy of a PVDF-TrFE film is formed selectively on the patterned rubrene with characteristic epitaxial crystal orientation over a large area.

ATP-Linked Chimeric Nucleotide as a Specific Luminescence Reporter of Deoxyuridine Triphosphatase.

Nucleotide surveillance enzymes play important roles in human health, by monitoring damaged monomers in the nucleotide pool and deactivating them before they are incorporated into chromosomal DNA or disrupt nucleotide metabolism. In particular, deamination of cytosine, leading to uracil in DNA and in the nucleotide pool, can be deleterious, causing DNA damage. The enzyme deoxyuridine triphosphatase (dUTPase) is currently under study as a therapeutic and prognostic target for cancer. Measuring the activity of this enzyme is important both in basic research and in clinical applications involving this pathway, but current methods are nonselective, detecting pyrophosphate, which is produced by many enzymes. Here we describe the design and synthesis of a dUTPase enzyme-specific chimeric dinucleotide (DUAL) that replaces the pyrophosphate leaving group of the native substrate with ATP, enabling sensitive detection via luciferase luminescence signaling. The DUAL probe functions sensitively and selectively to quantify enzyme activities in vitro and in cell lysates. We further report the first measurements of dUTPase activities in eight different cell lines, which are found to vary by a factor of 7-fold. We expect that the new probe can be of considerable utility in research involving this clinically significant enzyme.

Learning, memory deficits, and impaired neuronal maturation attributed to acrylamide.

Acrylamide (ACR) is a neurotoxin known to produce neurotoxicity characterized by ataxia, skeletal muscle weakness, cognitive impairment, and numbness of the extremities. Previously, investigators reported that high-dose (50 mg/kg) ACR impaired hippocampal neurogenesis and increased neural progenitor cell death; however, the influence of subchronic environmentally relevant low dose-(2, 20, or 200 µg/kg) ACRs have not been examined in adult neurogenesis or cognitive function in mice. Accordingly, the aim of the present study was to investigate whether low-dose ACR adversely affected mouse hippocampal neurogenesis and neurocognitive functions. Male C57BL/6 mice were orally administered vehicle or ACR at 2, 20, or 200 µg/kg/day for 4 weeks. ACR did not significantly alter the number of newly generated cells or produce neuroinflammation or neuronal loss in hippocampi. However, behavioral studies revealed that 200 µg/kg ACR produced learning and memory impairment. Furthermore, incubation of ACR with primary cultured neurons during the developmental stage was found to delay neuronal maturation without affecting cell viability indicating the presence of developmental neurotoxicity. These findings indicate that although exposure to in vivo low-dose ACR daily for 4 weeks exerted no apparent marked effect on hippocampal neurogenesis, in vitro observations in primary cultured neurons noted adverse effects on learning and memory impairment suggestive of neurotoxic actions.

Pseudane-VII Regulates LPS-Induced Neuroinflammation in Brain Microglia Cells through the Inhibition of iNOS Expression.

We previously isolated pseudane-VII from the secondary metabolites of Pseudoalteromonas sp. M2 in marine water, and demonstrated its anti-inflammatory efficacy on macrophages. However, the molecular mechanism by which pseudane-VII suppresses neuroinflammation has not yet been elucidated in brain microglia. Microglia is activated by immunological stimulation or brain injury. Activated microglia secrete proinflammatory mediators which damage neurons. Neuroinflammation appears to be associated with certain neurological diseases, including Parkinson's disease and Alzheimer's disease. Natural compounds that suppress microglial inflammatory responses could potentially be used to prevent neurodegenerative diseases or slow their progression. In the present study, we found that pseudane-VII suppresses neuroinflammation in lipopolysaccaride (LPS)-stimulated BV-2 microglial cells and brain. Pseudane-VII was shown to inhibit the LPS-stimulated NO, ROS production and the expression of iNOS and COX-2. To identify the signaling pathway targeted by pseudane-VII, we used western blot analysis to assess the LPS-induced phosphorylation state of p38, ERK1/2, JNK1/2, and nuclear factor-kappaB (NF-κB). We found that pseudane-VII attenuated LPS-induced phosphorylation of MAPK and NF-κB. Moreover, administration of pseudane-VII in mice significantly reduced LPS-induced iNOS expression and microglia activation in brain. Taken together, our findings suggest that pseudane-VII may represent a potential novel target for treatment for neurodegenerative diseases.

DNA-Catalyzed DNA Cleavage by a Radical Pathway with Well-Defined Products.

We describe an unprecedented DNA-catalyzed DNA cleavage process in which a radical-based reaction pathway cleanly results in excision of most atoms of a specific guanosine nucleoside. Two new deoxyribozymes (DNA enzymes) were identified by in vitro selection from N40 or N100 random pools initially seeking amide bond hydrolysis, although they both cleave simple single-stranded DNA oligonucleotides. Each deoxyribozyme generates both superoxide (O2-• or HOO•) and hydrogen peroxide (H2O2) and leads to the same set of products (3'-phosphoglycolate, 5'-phosphate, and base propenal) as formed by the natural product bleomycin, with product assignments by mass spectrometry and colorimetric assay. We infer the same mechanistic pathway, involving formation of the C4' radical of the guanosine nucleoside that is subsequently excised. Consistent with a radical pathway, glutathione fully suppresses catalysis. Conversely, adding either superoxide or H2O2 from the outset strongly enhances catalysis. The mechanism of generation and involvement of superoxide and H2O2 by the deoxyribozymes is not yet defined. The deoxyribozymes do not require redox-active metal ions and function with a combination of Zn2+ and Mg2+, although including Mn2+ increases the activity, and Mn2+ alone also supports catalysis. In contrast to all of these observations, unrelated DNA-catalyzed radical DNA cleavage reactions require redox-active metals and lead to mixtures of products. This study reports an intriguing example of a well-defined, DNA-catalyzed, radical reaction process that cleaves single-stranded DNA and requires only redox-inactive metal ions.

One-step construction of a molybdenum disulfide/multi-walled carbon nanotubes/polypyrrole nanocomposite biosensor for the ex-vivo detection of dopamine in mouse brain tissue.

We developed a new strategy for construction of a biosensor for the neurotransmitter dopamine. The biosensor was constructed by one-step electrochemical deposition of a nanocomposite in aqueous solution at pH 7.0, consisting of molybdenum disulfide, multi-walled carbon nanotubes, and polypyrrole. A series of analytical methods was performed to investigate the surface characteristics and the improved electrocatalytic effect of the nanocomposite, including cyclic voltammetry, electrochemical impedance spectroscopy, field-emission scanning electron microscopy, atomic force microscopy, and Raman spectroscopy. The constructed biosensor showed high sensitivity (1.130 µAµM-1cm-2) with a dynamic linearity range of 25-1000 nM and a detection limit of 10 nM. Additionally, the designed sensor exhibited strong anti-interference ability and satisfactory reproducibility. The practical application of the sensor was manifested for the ex vivo determination of dopamine neurotransmitters using brain tissue samples of a mouse Parkinson's disease model.

DNA-Catalyzed Amide Hydrolysis.

DNA catalysts (deoxyribozymes) for a variety of reactions have been identified by in vitro selection. However, for certain reactions this identification has not been achieved. One important example is DNA-catalyzed amide hydrolysis, for which a previous selection experiment instead led to DNA-catalyzed DNA phosphodiester hydrolysis. Subsequent efforts in which the selection strategy deliberately avoided phosphodiester hydrolysis led to DNA-catalyzed ester and aromatic amide hydrolysis, but aliphatic amide hydrolysis has been elusive. In the present study, we show that including modified nucleotides that bear protein-like functional groups (any one of primary amino, carboxyl, or primary hydroxyl) enables identification of amide-hydrolyzing deoxyribozymes. In one case, the same deoxyribozyme sequence without the modifications still retains substantial catalytic activity. Overall, these findings establish the utility of introducing protein-like functional groups into deoxyribozymes for identifying new catalytic function. The results also suggest the longer-term feasibility of deoxyribozymes as artificial proteases.

Neuroprotective and anti-inflammatory effects of morin in a murine model of Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that oxidative stress, mitochondrial dysfunction, and inflammation are associated with its pathogenesis. Morin (3,5,7,2',4'-pentahydroxyflavone) is a flavonol found in wine and many herbs and fruits. Previous studies have suggested that morin prevents oxidative damage and inflammation and ameliorates mitochondrial dysfunction. The present study describes the neuroprotective effects of morin in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, and we report the results of our investigation into its neuroprotective mechanism in primary neurons and astrocytes. In the mouse model, morin pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in SN and striatum, and alleviated MPTP-induced astrocyte activation. In vitro studies revealed that morin protected primary cultured neurons against 1-methyl-4-phenylpyridine (MPP(+) )-mediated reactive oxygen species production and mitochondrial membrane potential (MMP) disruption. In addition, morin effectively reduced MPP(+) -induced astroglial activation and nuclear translocation of nuclear factor-κB in primary cultured astrocytes. These results indicate that morin acts via multiple neuroprotective mechanisms in our mouse model and suggest that morin be viewed as a potential treatment and preventative for PD. © 2016 Wiley Periodicals, Inc.

5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against cancer cells.

Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (Sutent®) is an antitumor agent targeting receptor tyrosine kinases which are involved in angiogenesis as well as cancer cell growth and survival. Using the pyridin-3-ol scaffold, which was previously reported as an excellent antioxidant and antiangiogenic platform, we have synthesized sunitinib mimics 6 by hybridizing bicyclic pyridinol 4 as a key scaffold and pyrrole-2-carbaldehydes 7 as side chains. Cytotoxicity assays showed that compounds 6 have comparable to better anticancer activity than sunitinib against five different cancer cell lines. In addition, compounds 6 showed even lower levels of cytotoxicity against normal cells, resulting in up to 26-fold better safety windows, than sunitinib. Signaling pathway-associated transcription factor reporter assay and western blot analyses revealed that apoptosis induction in MDA-MB-231 human breast cancer cells by 6F is mainly mediated through the p53 increase and down-regulation of phospho-signal transducer and activator of transcription 3 (STAT3) and its target gene products, cyclin D, Bcl-2, and survivin. The data strongly suggest that our hybrid compounds can provide a novel anticancer scaffold with improved and safer cytotoxicity profiles than sunitinib.

Silibinin prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease via mitochondrial stabilization.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the nigrostriatal pathway. The lipophile 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can cross the blood-brain barrier and is subsequently metabolized into toxic1-methyl-4-phenylpyridine (MPP(+) ), which causes mitochondrial dysfunction and the selective cell death of dopaminergic neurons. The present article reports the neuroprotective effects of silibinin in a murine MPTP model of PD. The flavonoid silibinin is the major active constituent of silymarin, an extract of milk thistle seeds, and is known to have hepatoprotective, anticancer, antioxidative, and neuroprotective effects. In the present study, silibinin effectively attenuated motor deficit and dopaminergic neuronal loss caused by MPTP. Furthermore, in vitro study confirmed that silibinin protects primary cultured neurons against MPP(+) -induced cell death and mitochondrial membrane disruption. The findings of the present study indicate that silibinin has neuroprotective effects in MPTP-induced models of PD rather than antioxidative or anti-inflammatory effects and that the neuroprotection afforded might be mediated by the stabilization of mitochondrial membrane potential. Furthermore, these findings suggest that silibinin protects mitochondria in MPTP-induced PD models and that it offers a starting point for the development of treatments that ameliorate the symptoms of PD.

Baicalein attenuates astroglial activation in the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson's disease model by downregulating the activations of nuclear factor-κB, ERK, and JNK.

In Parkinson's disease (PD), neuroinflammation plays a critical role in the neurodegenerative process. Furthermore, activated microglia and astrocytes, responsible for activated immune response in the central nervous system, are found in regions associated with dopaminergic neuronal death. The flavonoid baicalein is known to have antibacterial, antiviral, and antiinflammatory activities. In the present study, the neuroprotective effects of baicalein were examined in a murine 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) model of PD. Low doses of baicalein improved motor ability and prevented dopaminergic neuron loss caused by MPTP. In addition, microglial and astrocyte activations were reduced in PD mice pretreated with baicalein. Further study of primary astrocytes revealed that baicalein suppressed the 1-methyl-4-phenylpyridine-induced nuclear translocation of nuclear factor-κB and reduced the activations of JNK and ERK, suggesting that the neuroprotective effects of baicalein in our PD model were due to attenuated astrocyte activation. The findings of this study indicate that baicalein could be useful for the treatment of PD and other neuroinflammation-related neurodegenerative diseases.

Growth of long triisopropylsilylethynyl pentacene (TIPS-PEN) nanofibrils in a polymer thin film during spin-coating.

This study demonstrates the growth of long triisopropylsilyethynyl pentacene (TIPS-PEN) nanofibrils in a thin film of a crystalline polymer, poly(ε-caprolactone) (PCL). During spin-coating, TIPS-PEN molecules are locally extracted around the PCL grain boundaries and they crystallize into [010] direction forming long nanofibrils. Molecular weight of PCL and weight fraction (α) of TIPS-PEN in PCL matrix are key factors to the growth of nanofibrils. Long high-quality TIPS-PEN nanofibrils are obtained with high-molecular-weight PCL and at the α values in the range of 0.03-0.1. The long nanofibrils are used as an active layer in a field-effect organic transistor.

Accelerating metal nanoparticle exsolution by exploiting tolerance factor of perovskite stannate.

The octahedral symmetry in ionic crystals can play a critical role in atomic nucleation and migration during solid-solid phase transformation. Similarly, octahedron distortion, which is characterized by Goldschmidt tolerance factor, strongly influences the exsolution kinetics in the perovskite lattice framework during high-temperature annealing. However, a fundamental study on manipulating the exsolution process by octahedron distortion is still lacking. In this study, we accelerate Ni metal exsolution on the surface of perovskite stannates by increasing the [BO6] octahedron distortion in the lattices. Decreasing the A-site ionic radius (rBa2+ = 161 pm → rSr2+ = 144 pm → rCa2+ = 134 pm) increased the density of exsolved Ni nanoparticles by up to 640% (i.e., 47 particles µm-2 of Ba(Sn, Ni)O3 → 304 particles µm-2 of Ca(Sn, Ni)O3) after the identical exsolution process. Based on the theoretical calculation and experimental characterization, the decrease in crystal symmetry by octahedral distortion promoted the Ni exsolution owing to the boosted Ni migration by weakening the bond strength and generating domain boundaries. The findings highlight the importance of octahedral distortion to control atomic migration through the perovskite lattice framework and provide a strategy to tailor the density of uniformly populated nanoparticles in nanocomposite oxides for multifunctional material design.