Browsing by Author "Liaw, Wen-Feng"

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A Dinitrosyliron Complex within the Homoleptic Fe(NO)(4) Anion: NO as Nitroxyl and Nitrosyl Ligands within a Single Structure
(2012-10-01)
Lin, Zong-Sian
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Chiou, Tzung-Wen
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Liu, Kuan-Yu
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Hsieh, Chang-Chih
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Yu, Jen-Shiang K.
Nitrosylation of the chelate thiolate-containing dinitrosyliron complex (DNIC) [(S(CH2)(3)S)Fe-(NO)(2)](-) triggers nitric oxide (NO) activation to generate the homoleptic nitrosyl {Fe(NO)(2)}(9) DNIC [Fe(NO)(4)](-) (1) made up of two nitroxyls (or two NO anions) attached to a delocalized {Fe(NO)(2)}(9) motif. The significantly longer N3-O3/N4-O4 [1.380(12) and 1.280(12) angstrom] and Fe1-N3/Fe1-N4 [2.008(11) and 2.045(10) angstrom] bond distances reflect that N3-O3 and N4-O4 of complex 1 may act as the nitroxyl-coordinated ligands. That is, the electronic structure of the DNIC 1 is best described as a {Fe(NO)(2)}(9) motif coordinated by two nitroxyl (NO-) ligands.
A N-(2-Aminophenyl)-5-(dimethylamino)-1-naphthalenesulfonic Amide (Ds-DAB) Based Fluorescent Chemosensor for Peroxynitrite
(2013-08-16)
Lin, Ku-Kuei
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Wu, Shou-Cheng
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Hsu, Kuang-Mei
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Hung, Chen-Hsiung
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Liaw, Wen-Feng
A dansyl derivative (Ds-DAB) was prepared and used as a fluorescent probe for peroxynitrite (ONOO-) detection. The results showed that the addition of peroxynitrite to the aqueous solution of Ds-DAB would result in obvious fluorescence enhancement. This probe is highly specific for peroxynitrite in aqueous solution, avoiding interference from other reactive oxygen species (ROS) and nitrogen species (RNS). The advantages of high selectivity, fast reaction rate, and peroxynitrite bioimaging render Ds-DAB suitable for peroxynitrite detection.
Activation of Angiogenesis and Wound Healing in Diabetic Mice Using NO-Delivery Dinitrosyl Iron Complexes
(2019-10-01)
Chen, Yu-Jen
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Wu, Shou-Cheng
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Wang, Hsiang-Ching
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Wu, Tung-Ho
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Yuan, Shyng-Shiou F.
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 [Fe-2(mu-SCH2CH2OH)(2)(NO)(4)] (DNIC-1) with a sustainable NO-release reactivity (t(1/2) = 27.4 +/- 0.5 h at 25 degrees C and 16.8 +/- 1.8 h at 37 degrees C) activates the NO-sGC-cGMP pathway and displays the best proangiogenesis 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)-N-center dot-release reactivity on the activation of angiogenesis and wound healing.
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!
(2018-10-15)
Lu, Tsai-Te
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Wang, Yun-Ming
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Hung, Chen-Hsiung
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Chiou, Show-Jen
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Liaw, Wen-Feng
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)-N-center dot/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-center dot] <-> {Fe(NO)(2)}(9) <-> {Fe(NO)(2)}(10) <-> [{Fe(NO)(2)}(10)-L-center dot](-) 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.
Dinitrosyliron Complex [(PMDTA)Fe(NO)(2)]: Intermediate for Nitric Oxide Monooxygenation Activity in Nonheme Iron Complex
(2020-06-15)
Lu, Shan
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Chiou, Tzung-Wen
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Li, Wei-Liang
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Wang, Chun-Chieh
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Wang, Yun-Ming
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 O-2 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 O-2 reactivity disclosed a conceivable pathway for aerobic metabolism of NO. During the NO-to-NO2-/NO3- conversion, transient formation of metal-bound peroxynitrite and subsequent release of (NO2)-N-center dot 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(kappa(2) -O,O'- NO2)(kappa(1) -O-NO2)] (3; PMDTA = pentamethyldiethylenetriamine) with NO(g), KC8, and O-2 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(kappa(2)-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.
Extension of C-elegans lifespan using the center dot NO-delivery dinitrosyl iron complexes
(2018-07-01)
Huang, Hsiao-Wen
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Lin, Yen-Hung
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Lin, Min-Hsuan
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Huang, Ya-Rong
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Chou, Chih-Hung
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 center dot 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) [Fe-2(mu-SR)(2)(NO)(4)] (1) as a universal platform for the O-2-triggered release of center dot NO, for the regulation of center dot NO-release kinetics (half-life = 0.6-27.4 h), and for the activation of physiological function of center dot NO. Using C. elegans as a model organism, the center dot 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-beta gal activity assay, and next-generation RNA sequencing analysis. This study unveils the anti-aging effect of center dot NO and develops DNICs as a chemical biology probe for the continued discovery of unprecedented NO physiology. [GRAPHICS] .
In Vitro and in Vivo Imaging of Nitroxyl with Copper Fluorescent Probe in Living Cells and Zebrafish
(2018-10-01)
Palanisamy, Sathyadevi
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Wang, Yu-Liang
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Chen, Yu-Jen
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Chen, Chiao-Yun
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Tsai, Fu-Te
Nitroxyl (HNO) plays a critical role in many physiological processes which includes vasorelaxation in heart failure, neuroregulation, and myocardial contractility. Powerful imaging tools are required to obtain information for understanding the mechanisms involved in these in vivo processes. In order to develop a rapid and high sensitive probe for HNO detection in living cells and the zebrafish model organism, 2-((2-(benzothiazole-2yl)benzylidene) amino)benzoic acid (AbTCA) as a ligand, and its corresponding copper(II) complex Cu(II)-AbTCA were synthesized. The reaction results of Cu(II)-AbTCA with Angeli's salt showed that Cu(II)-AbTCA could detect HNO quantitatively in a range of 40-360 mu M with a detection limit of 9.05 mu M. Furthermore, Cu(II)-AbTCA is more selective towards HNO over other biological species including thiols, reactive nitrogen, and reactive oxygen species. Importantly, Cu(II)-AbTCA was successfully applied to detect HNO in living cells and zebrafish. The collective data reveals that Cu(II)-AbTCA could be used as a potential probe for HNO detection in living systems.
Iron(III) Bound by Hydrosulfide Anion Ligands: NO-Promoted Stabilization of the [Fe-III-SH] Motif
(2014-07-02)
Tsou, Chih-Chin
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Chiu, Wei-Chun
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Ke, Chun-Hung
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Tsai, Jia-Chun
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Wang, Yun-Ming
Spontaneous transformation of the thermally stable [HS](-)bound {Fe(NO)(2)}(9) dinitrosyl iron complex (DNIC) [(HS)(2)Fe(NO)(2)](-) (1) into [(NO)(2)Fe(mu-S)](2)(2-) (Roussin's red salt (RRS)) along with release of H2S, probed by NBD-SCN (NBD = nitrobenzofurazan), was observed when DNIC 1 was dissolved in water at ambient temperature. The reversible transformation of RRS into DNIC 1 (RRS -> DNIC 1) in the presence of H2S was demonstrated. In contrast, the thermally unstable hydrosulfide-containing mononitrosyl iron complex (MNIC) [(HS)(3)Fe-III(NO)](-) (3) and [Fe-III(SH)(4)](-) (5) in THF/DMF spontaneously dimerized into the first structurally characterized Fe-III-hydrosulfide complexes [(NO)(SH)Fe(mu-S)](2)(2-) (4) with two {Fe(NO)}(7) motifs antiferromagnetically coupled and [(SH)(2)Fe(mu-S)](2)(2-) (6) resulting from two Fe-III (S = 5/2) centers antiferromagnetically coupled to yield an S = 0 ground state with thermal occupancy of higher spin states, respectively. That is, the greater the number of NO ligands bound to [2Fe2S], the larger the antiferromagnetic coupling constant. On the basis of DFT computation and the experimental (and calculated) reduction potential (E-1/2) of complexes 1, 3, and 5, the NO-coordinate ligand(s) of complexes 1 and 3 serves as the stronger electron-donating ligand, compared to thiolate, to reduce the effective nuclear charge (Z(eff)) of the iron center and prevent DNIC 1 from dimerization in an organic solvent (MeCN).
Iron(III) Bound by Hydrosulfide Anion Ligands: NO-Promoted Stabilization of the [Fe-III-SH] Motif
(2014-07-02)
Tsou, Chih-Chin
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Chiu, Wei-Chun
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Ke, Chun-Hung
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Tsai, Jia-Chun
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Wang, Yun-Ming
Spontaneous transformation of the thermally stable [HS](-)bound {Fe(NO)(2)}(9) dinitrosyl iron complex (DNIC) [(HS)(2)Fe(NO)(2)](-) (1) into [(NO)(2)Fe(mu-S)](2)(2-) (Roussin\'s red salt (RRS)) along with release of H2S, probed by NBD-SCN (NBD = nitrobenzofurazan), was observed when DNIC 1 was dissolved in water at ambient temperature. The reversible transformation of RRS into DNIC 1 (RRS -> DNIC 1) in the presence of H2S was demonstrated. In contrast, the thermally unstable hydrosulfide-containing mononitrosyl iron complex (MNIC) [(HS)(3)Fe-III(NO)](-) (3) and [Fe-III(SH)(4)](-) (5) in THF/DMF spontaneously dimerized into the first structurally characterized Fe-III-hydrosulfide complexes [(NO)(SH)Fe(mu-S)](2)(2-) (4) with two {Fe(NO)}(7) motifs antiferromagnetically coupled and [(SH)(2)Fe(mu-S)](2)(2-) (6) resulting from two Fe-III (S = 5/2) centers antiferromagnetically coupled to yield an S = 0 ground state with thermal occupancy of higher spin states, respectively. That is, the greater the number of NO ligands bound to [2Fe2S], the larger the antiferromagnetic coupling constant. On the basis of DFT computation and the experimental (and calculated) reduction potential (E-1/2) of complexes 1, 3, and 5, the NO-coordinate ligand(s) of complexes 1 and 3 serves as the stronger electron-donating ligand, compared to thiolate, to reduce the effective nuclear charge (Z(eff)) of the iron center and prevent DNIC 1 from dimerization in an organic solvent (MeCN).
Nitric Oxide Turn-on Fluorescent Probe Based on Deamination of Aromatic Primary Monoamines
(2012-05-07)
Shiue, Tsun-Wei
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Chen, Yen-Hao
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Wu, Chi-Ming
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Singh, Gyan
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Chen, Hsing-Yin
The stable, water-soluble, and nonfluorescent FA-OMe can sense nitric oxide (NO) and form the intensely fluorescent product dA-FA-OMe via reductive deamination of the aromatic primary amine. The reaction is accompanied by a notable increase of the fluorescent quantum yield from 1.5 to 88.8%. The deamination mechanism of FA-OMe with NO was proposed in this study. The turn-on fluorescence signals were performed by suppression of photoinduced electron transfer (PeT), which was demonstrated by density functional theory (DFT) calculations of the components forming FA-OMe and dA-FA-OMe. Furthermore, FA-OMe showed water solubility and good stability at physiological pHs. Moreover, the selectivity study indicated that FA-OMe had high specificity for NO over other reactive oxygen/nitrogen species. In an endogenously generated NO detection study, increasing the incubation time of FA-OMe with lipopolysaccharide (LPS) pretreated Raw 264.7 murine macrophages could cause an enhanced fluorescence intensity image. In addition, a diffusion/localization cell imaging study showed that FA-OMe could be trapped in Raw 264.7 cells. These cell imaging results demonstrated that FA-OMe could be used as a turn-on fluorescent sensor for the detection of endogenously generated NO.
Sensitivity evaluation of rhodamine B hydrazide towards nitric oxide and its application for macrophage cells imaging
(2011-12-05)
Wu, Chi-Ming
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Chen, Yen-Hao
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Dayananda, Kasala
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Shiue, Tsun-Wei
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Hung, Chen-Hsiung
A colorless and non-fluorescent rhodamine derivative, rhodamine B hydrazide (RH), is applied to detect nitric oxide and form fluorescent rhodamine B (RB). The reaction mechanism of RH with NO is proposed in this study. The probe shows good stability over a broad pH range (pH > 4). Furthermore, fluorescence intensity of RH displays an excellent linearity to the NO concentration and the detection limit is as low as 20 nM. A 1000-fold fluorescence turn-on from a dark background was observed. Moreover, the selectivity study indicated that the fluorescence intensity increasing in the presence of NO was significantly higher than those of other reactive oxygen/nitrogen species. In exogenously generated NO detection study, clear intracellular red fluorescence was observed in the presence of S-nitroso-N-acetyl-D,L-penicillamine (SNAP, a kind of NO releasing agent). In endogenously generated NO detection study, increasing incubation time of RH with lipopolysaccharied (LPS) pre-treated cells could obtain a highly fluorescent cell image. These cell imaging results demonstrated that RH can efficiently penetrate into Raw 264.7 cells and be used for detection of exogenously and endogenously generated nitric oxide. (C) 2011 Elsevier B.V. All rights reserved.
Water-Soluble Dinitrosyl Iron Complex (DNIC): a Nitric Oxide Vehicle Triggering Cancer Cell Death via Apoptosis
(2016-09-19)
Wu, Shou-Cheng
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Lu, Chung-Yen
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Chen, Yi-Lin
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Lo, Feng-Chun
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Wang, Ting-Yin
Nitric oxide (NO) is an important cellular signaling molecule that modulates various physiological activities. Angiogenesis-promoting activities of NO-donor drugs have been explored in both experimental and clinical studies. In this study, a structurally well characterized and water-soluble neutral {Fe-(NO)(2)}(9) DNIC [(S(CH2)(2)OH)(S(CH2)(2)NH3)Fe(NO)(2)] (DNIC 2) was synthesized to serve as a NO-donor species. The antitumor activity of DNIC 2 was determined by MTT assay, confocal imaging, and Annexin-V/PI staining. The IC50 values of DNIC 2 were 18.8, 42.9, and 38.6 mu M for PC-3, SKBR-3, and CRLS866 tumor cells, respectively. Moreover, DNIC 2 promoted apoptotic cell death via activation of apoptosis-associated proteins and inhibition of survival associated proteins. In particular, DNIC 2 treatment suppressed PC-3 tumor growth by 2.34- and 19.3-fold at 7 and 21 days, in comparison with the control group. These results indicate that water-soluble DNIC 2 may serve as a promising drug for cancer therapy.