Ligand Control of Dinitrosyl Iron Complexes for Selective Superoxide-Mediated Nitric Oxide Monooxygenation and Superoxide-Dioxygen Interconversion.

Through nitrosylation of [Fe-S] proteins, or the chelatable iron pool, a dinitrosyl iron unit (DNIU) [Fe(NO)2] embedded in the form of low-molecular-weight/protein-bound dinitrosyl iron complexes (DNICs) was discovered as a metallocofactor assembled under inflammatory conditions with elevated levels of nitric oxide (NO) and superoxide (O2-). In an attempt to gain biomimetic insights into the unexplored transformations of the DNIU under inflammation, we investigated the reactivity toward O2- by a series of DNICs [(NO)2Fe(µ-MePyr)2Fe(NO)2] (1) and [(NO)2Fe(µ-SEt)2Fe(NO)2] (3). During the superoxide-induced conversion of DNIC 1 into DNIC [(K-18-crown-6-ether)2(NO2)][Fe(µ-MePyr)4(µ-O)2(Fe(NO)2)4] (2-K-crown) and a [Fe3+(MePyr)x(NO2)y(O)z]n adduct, stoichiometric NO monooxygenation yielding NO2- occurs without the transient formation of peroxynitrite-derived •OH/•NO2 species. To study the isoelectronic reaction of O2(g) and one-electron-reduced DNIC 1, a DNIC featuring an electronically localized {Fe(NO)2}9-{Fe(NO)2}10 electronic structure, [K-18-crown-6-ether][(NO)2Fe(µ-MePyr)2Fe(NO)2] (1-red), was successfully synthesized and characterized. Oxygenation of DNIC 1-red leads to the similar assembly of DNIC 2-K-crown, of which the electronic structure is best described as paramagnetic with weak antiferromagnetic coupling among the four S = 1/2 {FeIII(NO-)2}9 units and S = 5/2 Fe3+ center. In contrast to DNICs 1 and 1-red, DNICs 3 and [K-18-crown-6-ether][(NO)2Fe(µ-SEt)2Fe(NO)2] (3-red) display a reversible equilibrium of "3 + O2- ⇋ 3-red + O2(g)", which is ascribed to the covalent [Fe(µ-SEt)2Fe] core and redox-active [Fe(NO)2] unit. Based on this study, the supporting/bridging ligands in dinuclear DNIC 1/3 (or 1-red/3-red) control the selective monooxygenation of NO and redox interconversion between O2- and O2 during reaction with O2- (or O2).

Sustained Releasable Copper and Zinc Biogenic Ions Co-Assembled in Metal-Organic Frameworks Reinforced Bacterial Eradication and Wound Mitigation in Diabetic Mice.

The employment of metal-organic framework (MOF)-based nanomaterials has been rapidly increasing in bioapplications owing to their biocompatibility, drug degradation, tunable porosity, and intrinsic biodegradability. This evidence suggests that the multifunctional bimetallic ions can behave as remarkable candidates for infection control and wound healing. In this study, bimetallic MOFs (Zn-HKUST-1 and FolA-Zn-HKUST-1) embedded with and without folic acid were synthesized and used for tissue sealing and repairing incisional wound sites in mice models. For comparison, HKUST-1 and FolA-HKUST-1 were also synthesized. The Brunauer-Emmett-Teller (BET) surface area measured for HKUST-1, FolA-HKUST-1, Zn-HKUST-1, and FolA-Zn-HKUST-1 from N2 isotherms was found to be 1868, 1392, 1706, and 1179 m2/g, respectively. The measurements of contact angle values for Zn-HKUST-1, FolA-HKUST-1, and Zn-FolA-HKUST-1 were identified as 4.95 ± 0.8, 43.6 ± 3.4, and 60.62 ± 2.0°, respectively. For topical application in wound healing, they display a wide range of healing characteristics, including antibacterial and enhanced wound healing rates. In addition, in vitro cell migration and tubulogenic potentials were evaluated. The significant reduction in the wound gap and increased expression levels for CD31, eNOS, VEGF-A, and Ki67 were observed from immunohistological analyses to predict the angiogenesis behavior at the incision wound site. The wound healing rate was analyzed in the excisional dermal wounds of diabetic mice model in vivo. On account of antibacterial potentials and tissue-repairing characteristics of Cu2+ and Zn2+ ions, designing an innovative mixed metal ion-based biomaterial has wide applicability and is expected to modulate the growth of various gradient tissues.

Substrate-Gated Transformation of a Pre-Catalyst into an Iron-Hydride Intermediate [(NO)2(CO)Fe(µ-H)Fe(CO)(NO)2]- for Catalytic Dehydrogenation of Dimethylamine Borane.

Continued efforts are made on the development of earth-abundant metal catalysts for dehydrogenation/hydrolysis of amine boranes. In this study, complex [K-18-crown-6-ether][(NO)2Fe(µ-MePyr)(µ-CO)Fe(NO)2] (3-K-crown, MePyr = 3-methylpyrazolate) was explored as a pre-catalyst for the dehydrogenation of dimethylamine borane (DMAB). Upon evolution of H2(g) from DMAB triggered by 3-K-crown, parallel conversion of 3-K-crown into [(NO)2Fe(N,N'-MePyrBH2NMe2)]- (5) and an iron-hydride intermediate [(NO)2(CO)Fe(µ-H)Fe(CO)(NO)2]- (A) was evidenced by X-ray diffraction/nuclear magnetic resonance/infrared/nuclear resonance vibrational spectroscopy experiments and supported by density functional theory calculations. Subsequent transformation of A into complex [(NO)2Fe(µ-CO)2Fe(NO)2]- (6) is synchronized with the deactivated generation of H2(g). Through reaction of complex [Na-18-crown-6-ether][(NO)2Fe(η2-BH4)] (4-Na-crown) with CO(g) as an alternative synthetic route, isolated intermediate [Na-18-crown-6-ether][(NO)2(CO)Fe(µ-H)Fe(CO)(NO)2] (A-Na-crown) featuring catalytic reactivity toward dehydrogenation of DMAB supports a substrate-gated transformation of a pre-catalyst [(NO)2Fe(µ-MePyr)(µ-CO)Fe(NO)2]- (3) into the iron-hydride species A as an intermediate during the generation of H2(g).

Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours.

OBJECTIVE: Stromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC. DESIGN: Nitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro-in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo. RESULTS: The delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy. CONCLUSION: The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.

One-Pot Photosynthesis of Cubic Fe@Fe3O4 Core-Shell Nanoparticle Well-Dispersed in N-Doping Carbonaceous Polymer Using a Molecular Dinitrosyl Iron Precursor.

Nanoscale zerovalent iron (NZVI) features potential application to biomedicine, (electro-/photo)catalysis, and environmental remediation. However, multiple-synthetic steps and limited ZVI content prompt the development of a novel strategy for efficient preparation of NZVI composites. Herein, a dinitrosyl iron complex [(N3MDA)Fe(NO)2] (1-N3MDA) was explored as a molecular precursor for one-pot photosynthesis of a cubic Fe@Fe3O4 core-shell nanoparticle (ZVI% = 60%) well-dispersed in an N-doping carbonaceous polymer (NZVI@NC). Upon photolysis of 1-N3MDA, photosensitizer Eosin Y, and sacrificial reductant TEA, the α-diimine N3MDA and noninnocent NO ligands (1) enable the slow reduction of 1-N3MDA into an unstable [(N3MDA)Fe(NO)2]- species, (2) serve as a capping reagent for controlled nucleation of zerovalent Fe atom into Fe nanoparticle, and (3) promote the polymerization of degraded Eosin Y with N3MDA yielding an N-doping carbonaceous matrix in NZVI@NC. This discovery of a one-pot photosynthetic process for NZVI@NC inspires continued efforts on its application to photolytic water splitting and ferroptotic chemotherapy in the near future.

Insight into the Electronic Structure of Biomimetic Dinitrosyliron Complexes (DNICs): Toward the Syntheses of Amido-Bridging Dinuclear DNICs.

The ubiquitous function of nitric oxide (NO) guided the biological discovery of the natural dinitrosyliron unit (DNIU) [Fe(NO)2] as an intermediate/end product after Fe nitrosylation of nonheme cofactors. Because of the natural utilization of this cofactor for the biological storage and delivery of NO, a bioinorganic study of synthetic dinitrosyliron complexes (DNICs) has been extensively explored in the last 2 decades. The bioinorganic study of DNICs involved the development of synthetic methodology, spectroscopic discrimination, biological application of NO-delivery reactivity, and translational application to the (catalytic) transformation of small molecules. In this Forum Article, we aim to provide a systematic review of spectroscopic and computational insights into the bonding nature within the DNIU [Fe(NO)2] and the electronic structure of different types of DNICs, which highlights the synchronized advance in synthetic methodology and spectroscopic tools. With regard to the noninnocent nature of a NO ligand, spectroscopic and computational tools were utilized to provide qualitative/quantitative assignment of oxidation states of Fe and NO in DNICs with different redox levels and ligation modes as well as to probe the Fe-NO bonding interaction modulated by supporting ligands. Besides the strong antiferromagnetic coupling between high-spin Fe and paramagnetic NO ligands within the covalent DNIU [Fe(NO)2], in polynuclear DNICs, the effects of the Fe···Fe distance, nature of the bridging ligands, and type of bridging modes on the regulation of the magnetic coupling among paramagnetic DNIU [Fe(NO)2] are further reviewed. In the last part of this Forum Article, the sequential reaction of {Fe(NO)2}10 DNIC [(NO)2Fe(AMP)] (1-red) with NO(g), HBF4, and KC8 establishes a synthetic cycle, {Fe(NO)2}9-{Fe(NO)2}9 DNIC [(NO)2Fe(µ-dAMP)2Fe(NO)2] (1) → {Fe(NO)2}9 DNIC [(NO2)Fe(AMP)][BF4] (1-H) → {Fe(NO)2}10 DNIC 1-red → DNIC 1, for the transformation of NO into HNO/N2O. Of importance, the NO-induced transformation of {Fe(NO)2}10 DNIC 1-red and [(NO)2Fe(DTA)] (2-red; DTA = diethylenetriamine) unravels a synthetic strategy for preparation of the {Fe(NO)2}9-{Fe(NO)2}9 DNICs [(NO)2Fe(µ-NHR)2Fe(NO)2] containing amido-bridging ligands, which hold the potential to feature distinctive physical properties, chemical reactivities, and biological applications.

Cell-Penetrating Delivery of Nitric Oxide by Biocompatible Dinitrosyl Iron Complex and Its Dermato-Physiological Implications.

After the discovery of endogenous dinitrosyl iron complexes (DNICs) as a potential biological equivalent of nitric oxide (NO), bioinorganic engineering of [Fe(NO)2] unit has emerged to develop biomimetic DNICs [(NO)2Fe(L)2] as a chemical biology tool for controlled delivery of NO. For example, water-soluble DNIC [Fe2(µ-SCH2CH2OH)2(NO)4] (DNIC-1) was explored for oral delivery of NO to the brain and for the activation of hippocampal neurogenesis. However, the kinetics and mechanism for cellular uptake and intracellular release of NO, as well as the biocompatibility of synthetic DNICs, remain elusive. Prompted by the potential application of NO to dermato-physiological regulations, in this study, cellular uptake and intracellular delivery of DNIC [Fe2(µ-SCH2CH2COOH)2(NO)4] (DNIC-2) and its regulatory effect/biocompatibility toward epidermal cells were investigated. Upon the treatment of DNIC-2 to human fibroblast cells, cellular uptake of DNIC-2 followed by transformation into protein-bound DNICs occur to trigger the intracellular release of NO with a half-life of 1.8 ± 0.2 h. As opposed to the burst release of extracellular NO from diethylamine NONOate (DEANO), the cell-penetrating nature of DNIC-2 rationalizes its overwhelming efficacy for intracellular delivery of NO. Moreover, NO-delivery DNIC-2 can regulate cell proliferation, accelerate wound healing, and enhance the deposition of collagen in human fibroblast cells. Based on the in vitro and in vivo biocompatibility evaluation, biocompatible DNIC-2 holds the potential to be a novel active ingredient for skincare products.

Lysophosphatidic acid improves corneal endothelial density in tissue culture by stimulating stromal secretion of interleukin-1ß.

The short supply of donor corneas is exacerbated by the unsuitability of donors with insufficient endothelial cell density. Few studies have investigated promoting corneal endothelial cell proliferation to increase the endothelial cell density. We hypothesize that pre-transplantation treatment of proliferative tissue-cultivated corneas may increase corneal endothelial cell density. We observed that the airlift cultures were superior to immersion cultures with respect to both transparency and thickness. In this tissue culture system, we observed that lysophosphatidic acid increased the rabbit corneal endothelial cell density, number of BrdU-positive cells and improve wound healing. We also observed an indirect effect of lysophosphatidic acid on corneal endothelial cell proliferation mediated by the stimulation of interleukin-1ß secretion from stromal cells. Human corneal tissues treated with lysophosphatidic acid or interleukin-1ß contained significantly more Ki-67-positive cells than untreated group. The lysophosphatidic acid- or interleukin-1ß-treated cultured tissue remained hexagon-shaped, with ZO-1 expression and no evidence of the endothelial-mesenchymal transition. Our novel protocol of tissue culture may be applicable for eye banks to optimize corneal grafting.

Dinitrosyliron Complex [(PMDTA)Fe(NO)2]: Intermediate for Nitric Oxide Monooxygenation Activity in Nonheme Iron Complex.

Despite a comprehensive study on the biosynthesis and function of nitric oxide, biological metabolism of nitric oxide, especially when its concentration exceeds the cytotoxic level, remains elusive. Oxidation of nitric oxide by O2 in aqueous solution has been known to yield NO2-. On the other hand, a biomimetic study on the metal-mediated conversion of NO to NO2-/NO3- via O2 reactivity disclosed a conceivable pathway for aerobic metabolism of NO. During the NO-to-NO3- conversion, transient formation of metal-bound peroxynitrite and subsequent release of •NO2 via O-O bond cleavage were evidenced by nitration of tyrosine residue or 2,4-di-tert-butylphenol (DTBP). However, the synthetic/catalytic/enzymatic cycle for conversion of nitric oxide into a nitrite pool is not reported. In this study, sequential reaction of the ferrous complex [(PMDTA)Fe(κ2-O,O'-NO2)(κ1-O-NO2)] (3; PMDTA = pentamethyldiethylenetriamine) with NO(g), KC8, and O2 established a synthetic cycle, complex 3 → {Fe(NO)2}9 DNIC [(PMDTA)Fe(NO)2][NO2] (4) → {Fe(NO)2}10 DNIC [(PMDTA)Fe(NO)2] (1) → [(PMDTA)(NO)Fe(κ2-O,N-ONOO)] (2) → complex 3, for the transformation of nitric oxide into nitrite. In contrast to the reported reactivity of metal-bound peroxynitrite toward nitration of DTBP, peroxynitrite-bound MNIC 2 lacks phenol nitration reactivity toward DTBP. Presumably, the [(PMDTA)Fe] core in {Fe(NO)}8 MNIC 2 provides a mononuclear template for intramolecular interaction between Fe-bound peroxynitrite and Fe-bound NO-, yielding Fe-bound nitrite stabilized in the form of complex 3. This [(PMDTA)Fe]-core-mediated concerted peroxynitrite homolytic O-O bond cleavage and combination of the O atom with Fe-bound NO- reveals a novel and effective pathway for NO-to-NO2- transformation. Regarding the reported assembly of the dinitrosyliron unit (DNIU) [Fe(NO)2] in the biological system, this synthetic cycle highlights DNIU as a potential intermediate for nitric oxide monooxygenation activity in a nonheme iron system.

Accelerated corneal endothelial cell loss in two patients with granulomatosis with polyangiitis following phacoemulsification.

BACKGROUND: Generally, the loss rate of human endothelial cells (HCEC) in routine cataract surgery is 8.5%. When the corneal endothelial cells density (ECD) drops, the HCEC may decompensate to keep cornea dehydration which leads to corneal edema. Granulomatosis with polyangiitis (GPA) is an uncommon autoimmune disease involving multiple organs including eyes such as conjunctivitis, scleritis, uveitis, and corneal ulcer. In this study, we report two cases of GPA whose corneal ECD decreased significantly after phacoemulsification cataract surgery. CASE PRESENTATION: In the first case of 69-year-old male with GPA, the ECD dropped 39.6% (OD) four months after phacoemulsification and 38.1% (OS) six months postoperatively respectively. At the final follow-up, the residual ECD was only 55% in the right eye in the 49th month, and 56% remained in the left eye in the 39th month. In the second case of 54-year old female, left ECD dropped 63.9% at the 4th month after surgery and 69.6% ECD remained at the 15th month postoperatively while similar ECD of right eye before and after left eye surgery. CONCLUSION: Extensive preoperative ophthalmic evaluation and meticulous postoperative inflammation control should be applied to prevent severe loss of HCEC in GPA patients.

Dinitrosyl Iron Complex [K-18-crown-6-ether][(NO)2 Fe(Me PyrCO2 )]: Intermediate for Capture and Reduction of Carbon Dioxide.

Continued efforts are made for the utilization of CO2 as a C1 feedstock for regeneration of valuable chemicals and fuels. Mechanistic study of molecular (electro-/photo-)catalysts disclosed that initial step for CO2 activation involves either nucleophilic insertion or direct reduction of CO2 . In this study, nucleophilic activation of CO2 by complex [(NO)2 Fe(µ-Me Pyr)2 Fe(NO)2 ]2- (2, Me Pyr=3-methylpyrazolate) results in the formation of CO2 -captured complex [(NO)2 Fe(Me PyrCO2 )]- (2-CO2 , Me PyrCO2 =3-methyl-pyrazole-1-carboxylate). Single-crystal structure, spectroscopic, reactivity, and computational study unravels 2-CO2 as a unique intermediate for reductive transformation of CO2 promoted by Ca2+ . Moreover, sequential reaction of 2 with CO2 , Ca(OTf)2 , and KC8 established a synthetic cycle, 2 → 2-CO2 → [(NO)2 Fe(µ-Me Pyr)2 Fe(NO)2 ] (1) → 2, for selective conversion of CO2 into oxalate. Presumably, characterization of the unprecedented intermediate 2-CO2 may open an avenue for systematic evaluation of the effects of alternative Lewis acids on reduction of CO2 .

Synthetic methodology for preparation of dinitrosyl iron complexes.

After the first structural characterization of dinuclear dinitrosyl iron complex (DNIC) in 1958 and discovery of natural dinitrosyl iron unit (DNIU) [Fe(NO)2] in 1964-1965, continued investigations on natural and synthetic DNICs explored their ubiquitous functions as (1) a product for nitrosylation of non-heme Fe proteins and chelatable iron pool, (2) a biological vehicle for iron and nitric oxide, (3) a novel redox-active unit for stabilization and activation of small molecules, (4) an electrocatalyst for water splitting, and (5) a precursor for electrodeposition of Fe-containing hybrid material. From a synthetic chemistry perspective, herein, we summarize four synthetic methodologies for preparation of structure-characterized DNICs in the attempt to attract continued development of unexplored DNICs featuring novel functions. As collected from CCDC database, structure-characterized DNICs can be classified into (1) tetrahedral {Fe(NO)2}9 DNICs with C/N/P/O/S/Se/Cl/Br/I ligation modes, (2) five-/six-coordinate {Fe(NO)2}9 DNICs with N/O ligation modes, (3) tetrahedral {Fe(NO)2}10 DNICs with C/Sn/N/P/O/S/H ligation modes, (4) metallothiolate-bound {Fe(NO)2}9/{Fe(NO)2}10 DNICs, and (5) dinuclear {Fe(NO)2}9-{Fe(NO)2}9, {Fe(NO)2}9-{Fe(NO)2}10, and {Fe(NO)2}10-{Fe(NO)2}10 DNICs with thiolate/alkoxide/pyrazolate/CO bridging ligands. After buildup of the DNIU [Fe(NO)2] using NO, NO+, and NO2- as alternative sources of nitrosyl ligands, ligand substitution and modification reaction of DNICs, redox interconversion between {Fe(NO)2}9 and {Fe(NO)2}10 cores, and transformation between mononuclear and dinuclear DNICs establish the comprehensive pathways to bridge alternative types of DNICs in the chemical library of structure-characterized DNICs. This review on the synthetic methodology for preparation of DNICs will facilitate the incorporation of DNIU [Fe(NO)2] into (bio)materials for potential applications of DNICs in chemistry, catalysis, biology, and biomedicine.

Activation of Angiogenesis and Wound Healing in Diabetic Mice Using NO-Delivery Dinitrosyl Iron Complexes.

In diabetes, abnormal angiogenesis due to hyperglycemia and endothelial dysfunction impairs wound healing and results in high risks of diabetic foot ulcers and mortality. Alternative therapeutic methods were attempted to prevent diabetic complications through the activation of endothelial nitric oxide synthase. In this study, direct application of nitric oxide using dinitrosyl iron complexes (DNICs) to promote angiogenesis and wound healing under physiological conditions and in diabetic mice is investigated. Based on in vitro and in vivo studies, DNIC [Fe2(µ-SCH2CH2OH)2(NO)4] (DNIC-1) with a sustainable NO-release reactivity (t1/2 = 27.4 ± 0.5 h at 25 °C and 16.8 ± 1.8 h at 37 °C) activates the NO-sGC-cGMP pathway and displays the best pro-angiogenesis activity overwhelming other NO donors and the vascular endothelial growth factor. Moreover, this pro-angiogenesis effect of DNIC-1 restores the impaired angiogenesis in the ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates synthetic DNIC-1 into a novel therapeutic agent for the treatment of diabetes and highlights its sustainable •NO-release reactivity on the activation of angiogenesis and wound healing.

Extension of C. elegans lifespan using the ·NO-delivery dinitrosyl iron complexes.

The ubiquitous and emerging physiology function of endogenous nitric oxide in vascular, myocardial, immune, and neuronal systems prompts chemists to develop a prodrug for the controlled delivery of ·NO in vivo and for the translational biomedical application. Inspired by the discovery of natural [Fe(NO)2] motif, herein, we develop the synthetic dinitrosyl iron complexes (DNICs) [Fe2(µ-SR)2(NO)4] (1) as a universal platform for the O2-triggered release of ·NO, for the regulation of ·NO-release kinetics (half-life = 0.6-27.4 h), and for the activation of physiological function of ·NO. Using C. elegans as a model organism, the ·NO-delivery DNIC 1 regulates IIS signaling pathway, AMPK signaling pathway, and mitochondrial function pathway to extend the lifespan and to delay the aging process based on the lifespan analysis, SA-ßgal activity assay, and next-generation RNA sequencing analysis. This study unveils the anti-aging effect of ·NO and develops DNICs as a chemical biology probe for the continued discovery of unprecedented NO physiology.

Bioinorganic Chemistry of the Natural [Fe(NO)2] Motif: Evolution of a Functional Model for NO-Related Biomedical Application and Revolutionary Development of a Translational Model.

Identification of the distinctive electron paramagnetic resonance signal at g = 2.03 in the yeast cells and liver of mice treated with carcinogens opened the discovery and investigation of the natural [Fe(NO)2] motif in the form of dinitrosyliron complexes (DNICs). In this Viewpoint, a chronological collection of the benchmark for the study of DNIC demonstrates that the preceding study of its biological synthesis, storage, transport, transformation, and function related to NO physiology inspires the biomimetic study of structural and functional models supported by thiolate ligands to provide mechanistic insight at a molecular level. During the synthetic, spectroscopic, and theoretical investigations on the structure-to-reactivity relationship within DNICs, control of the Fe-NO bonding interaction and of the delivery of NO+/•NO/HNO/NO- by the supporting ligands and nuclearity evolves into the "redesign of the natural [Fe(NO)2] motif" as a strategy to develop DNICs for NO-related biomedical application and therapeutic approach. The revolutionary transformation of covalent a [Fe(NO)2] motif into a translational model for hydrogenase, triggered by the discovery of redox interconversion among [{Fe(NO)2}9-L•] ↔ {Fe(NO)2}9 ↔ {Fe(NO)2}10 ↔ [{Fe(NO)2}10-L•]-, echoes the preceding research journey on [Fe]/[NiFe]-hydrogenase and completes the development of an electrodeposited-film electrode for electrocatalytic water splitting. Through the 50-year journey, bioinorganic chemistry of DNIC containing the covalent [Fe(NO)2] motif and noninnocent/labile NO ligands highlights itself as a unique metallocofactor to join the longitudinal study between biology/chemistry/biomedical application and the lateral study toward multielectron (photo/electro)catalysis for industrial application. This Viewpoint discloses the potential [Fe(NO)2] motif awaiting continued contribution in order to emerge as a novel application in the next 50 years, whereas the parallel development of bioinorganic chemistry, guided by inspirational Nature, moves the science forward to the next stage in order to benefit the immediate needs for human activity.

To Transfer or Not to Transfer? Development of a Dinitrosyl Iron Complex as a Nitroxyl Donor for the Nitroxylation of an Fe(III) -Porphyrin Center.

A positive myocardial inotropic effect achieved using HNO/NO(-) , compared with NO⋅, triggered attempts to explore novel nitroxyl donors for use in clinical applications in vascular and myocardial pharmacology. To develop M-NO complexes for nitroxyl chemistry and biology, modulation of direct nitroxyl-transfer reactivity of dinitrosyl iron complexes (DNICs) is investigated in this study using a Fe(III) -porphyrin complex and proteins as a specific probe. Stable dinuclear {Fe(NO)2 }(9) DNIC [Fe(µ-(Me) Pyr)(NO)2 ]2 was discovered as a potent nitroxyl donor for nitroxylation of Fe(III) -heme centers through an associative mechanism. Beyond the efficient nitroxyl transfer, transformation of DNICs into a chemical biology probe for nitroxyl and for pharmaceutical applications demands further efforts using in vitro/in vivo studies.

Development of a Dinitrosyl Iron Complex Molecular Catalyst into a Hydrogen Evolution Cathode.

Despite extensive efforts, the electrocatalytic reduction of water using homogeneous/heterogeneous Fe, Co, Ni, Cu, W, and Mo complexes remains challenging because of issues involving the development of efficient, recyclable, stable, and aqueous-compatible catalysts. In this study, evolution of the de novo designed dinitrosyl iron complex DNIC-PMDTA from a molecular catalyst into a solid-state hydrogen evolution cathode, considering all the parameters to fulfill the electronic and structural requirements of each step of the catalytic cycle, is demonstrated. DNIC-PMDTA reveals electrocatalytic reduction of water at neutral and basic media, whereas its deposit on electrode preserves exceptional longevity, 139 h. This discovery will initiate a systematic study on the assembly of [Fe(NO)2] motif into current collector for mass production of H2, whereas the efficiency remains tailored by its molecular precursor [(L)Fe(NO)2].

X-ray emission spectroscopy: a spectroscopic measure for the determination of NO oxidation states in Fe-NO complexes.

Extensive study of the electronic structure of Fe-NO complexes using a variety of spectroscopic methods was attempted to understand how iron controls the binding and release of nitric oxide. The comparable energy levels of NO π* orbitals and Fe 3d orbitals complicate the bonding interaction within Fe-NO complexes and puzzle the quantitative assignment of NO oxidation state. Enemark-Feltham notation, {Fe(NO)x}(n), was devised to circumvent this puzzle. This 40-year puzzle is revisited using valence-to-core X-ray emission spectroscopy (V2C XES) in combination with computational study. DFT calculation establishes a linear relationship between ΔE(σ2s*-σ2p) of NO and its oxidation state. V2C Fe XES study of Fe-NO complexes reveals the ΔE(σ2s*-σ2p) of NO derived from NO σ(2s)*/σ(2p)→Fe(1s) transitions and determines NO oxidation state in Fe-NO complexes. Quantitative assignment of NO oxidation state will correlate the feasible redox process of nitric oxide and Fe-nitrosylation biology.

Cisplatin-activated and hemoglobin-mediated injectable hydrogel system for antitumor chemodynamic and chemotherapy.

Low specificity and hypoxia-induced drug resistance are significant challenges in traditional cancer treatment. To enhance the anticancer efficacy, an injectable hydrogel system is developed through the formation of dynamic covalent bonds in hyaluronic acid, allowing for localized controlled release of drugs. This system also utilizes double-stranded DNA sequences for the intercalation delivery of the chemotherapeutic drug, enabling a multifaceted approach to therapy. Cisplatin not only serves as a chemotherapy drug but also acts as a catalyst for chemodynamic therapy (CDT) to initiate CDT cascades by creating hydrogen peroxide for the Fenton reaction. Hemoglobin, enclosed in PLGA nanoparticles, provides ferrous ions that react with hydrogen peroxide in an acidic environment, yielding hydroxyl radicals that induce cancer cell death. Additionally, oxygen released from hemoglobin mitigates hypoxia-induced chemoresistance, bolstering overall anticancer efficacy. Results demonstrate the shear-thinning properties and injectability of the hydrogel. Cisplatin elevates intracellular hydrogen peroxide levels in tumor cells, while hemoglobin efficiently releases ferrous ions and generates reactive oxygen species (ROS) in the presence of hydrogen peroxide. In in vitro and in vivo study, the combinational use of chemo- and chemodynamic therapies achieves a synergistic anticancer effect on combating glioblastoma. In summary, our CDT-based hydrogel, activated by endogenous cues and mediated by chemo drugs, spontaneously produces ROS and ameliorates the adverse tumor microenvironment with rational and selective antitumor strategies.

Mechanistic and Kinetic Insights into Cellular Uptake of Biomimetic Dinitrosyl Iron Complexes and Intracellular Delivery of NO for Activation of Cytoprotective HO-1.

Dinitrosyl iron unit (DNIU), [Fe(NO)2], is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) [(NO)2Fe(µ-SCH2CH2COOH)2Fe(NO)2] (DNIC-COOH) and [(NO)2Fe(µ-SCH2CH2COOCH3)2Fe(NO)2] (DNIC-COOMe) were employed to investigate the structure-reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC-COOMe through a thiol-mediated pathway (tmax = 0.5 h), intracellular assembly of mononuclear DNIC [(NO)2Fe(SR)(SCys)]n-/[(NO)2Fe(SR)(SCys-protein)]n- occurred, followed by O2-induced release of free NO (tmax = 1-2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC-COOH via endocytosis (tmax = 2-8 h) and for intracellular release of NO (tmax = 4-6 h) reflected on the elevated activation of cytoprotective HO-1 (∼50-150-fold change at t = 3-10 h) and on the improved survival of DNIC-COOH-primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC-COOH/DNIC-COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine.