archives@tulane.edu / This dissertation is dedicated to the study of the synthesis, crystal structures, properties, and reactivity of heteroleptic metallodithiolene complexes of the Group 10 metals. In this work, we report a systematic survey of the reactivity of [(Ph2C2S2)2M] (M = Ni, Pd, Pt) toward ligand substitution. The upshots of the survey are the clarification of the attributes of the incoming ligand that facilitate ligand displacement, creation of a new set of heteroleptic dithiolene complexes, [M(Ph2C2S2)(C≡NR)2] (M = Ni, Pd, Pt; R = Me, Bn, Cy, tBu, 1-Adamantyl, Ph), and improvement in the efficiency by which mixed-ligand “push-pull” compounds are made. The scope of dithiolene ligand displacement by incoming ligands was expanded beyond the already reported phosphine and diimine ligands. Spectroscopic and physical characterization techniques including S K-edge X-ray absorption spectroscopy (XAS) and X-ray diffraction (XRD) were used in conjunction with DFT computational methods to establish the properties of the compounds prepared in this study. Representative [(Ph2C2S2)Pt(C≡NR)2] (R = aryl) complexes exihibited low temperature luminscence in frozen solvent glasses with relatively long lifetimes. The relevance of the dithiolene redox non-innocence in the ligand substitution mechanism has also been elucidated, thereby giving an insight into the fate of the displaced dithiolene ligand. Redox disproportionation between two radical monoanionic dithiolene ligands leads to the creation of a dithione, which is an enhanced leaving group and an inherently reactive species. When displacement of dithiolene ligand from [(Ph2C2S2)2Ni] was conducted with a twofold excess of C≡NCy, 4,5-diphenyl-1,3-dithiol-2-cyclohexylimine could be isolated. The identification and characterization of this compound is consistent with the creation of dithiobenzil during the ligand substitution. The reactive α-dithione is also capable of undergoing rapid irreversible polymerization, thereby providing the thermodynamic impetus for the dithiolene ligand substitution. Chemical oxidation of [Pt(Ph2C2S2)(C≡NtBu)2] with [N(C6H4Br-4)3][SbCl6] was undertaken to form [Pt(Ph2C2SˉS‧)(C≡NtBu)2]2[SbCl6]2. Structural determination of the dication revealed appreciable shortening and lengthening of C─S and C─C bond distances, respectively, within the dithiolene ligand as compared to the charge-neutral complex, an observation which confirmed the dithiolene ligand as the locus of the redox activity in the heteroleptic monodithiolene complexes. The utility of [M(Ph2C2S2)(C≡NMe)2] (M= Ni, Pd, Pt) as synthons in their own right for heteroleptic compounds not directly attainable by ligand substitution from [M(Ph2C2S2)2] was also explored. The panorama of outcomes when [M(S2C2Ph2)(CNMe)2] (M = Ni2+, Pd2+, Pt2+) are introduced to new ligands intended to substitute for CNMe has been thoroughly defined. The most significant breakthrough was the isolation of the dicyanide complex, [Et4N]2[Ni(S2C2Ph2)(C≡N)2], which is a potentially useful precursor toward cyanide-bridged multimetallic architectures. Finally, the synthesis and structural characterization of multimetallic complexes bridged by bis(diphenylphosphine) ligands and redox active dithiolenes as end capping ligands are described. The electrochemistry study revealed that the dimetallic compounds support reversible oxidation to dications, which likely have singlet diradical - triplet states in close equilibrium. The use of dithiolene ligands as electron spin hosts offers new possibilities for the application of metallodithiolene complexes in molecule-based spintronic devices, such as quantum bits (qubits). / 1 / Antony Obanda

Oxidative stress is a hallmark of several aging and trauma related neurological disorders, but the precise details of how altered neuronal activity elicits subcellular redox changes have remained difficult to resolve. Current redox sensitive dyes and fluorescent proteins can quantify spatially distinct changes in reactive oxygen species levels, but multicolor probes are needed to accurately analyze compartment-specific redox dynamics in single cells that can be masked by population averaging. Our lab previously engineered a genetically-encoded red-shifted redox-sensitive fluorescent protein sensors using a Förster resonance energy transfer relay strategy. Here, we developed a second-generation excitation ratiometric sensor called rogRFP2 with improved red emission for quantitative live-cell imaging. Using this sensor to measure activity-dependent redox changes in individual cultured neurons, we observed an anticorrelation in which mitochondrial oxidation was accompanied by a concurrent reduction in the cytosol. This behavior was dependent on the activity of Complex I of the mitochondrial electron transport chain and could be modulated by the presence of co-cultured astrocytes. We also demonstrated that the red fluorescent rogRFP2 facilitates ratiometric redox imaging in Drosophila retinas. The proof-of-concept studies reported here demonstrate that this new rogRFP2 redox sensor can be a powerful tool for understanding redox biology both in vitro and in vivo across model organisms. In addition, we have used these tools that monitor cellular redox, to study oxidative stress and ROS changes in Parkinson’s disease models. Here, we have established cellular models for studying Parkinson’s disease causing LRRK2 mutations to create a platform for future work to explore the relationship between PD associated LRRK2 variants and oxidative stress.

The chemistry of transition metal clusters has been a fast developing area of organometallic research in recent years. Compared to mononuclear metal complexes, polynuclear clusters offer more opportunities to study cooperative effects and electron reservoir properties between contiguous metal centers, in addition to functioning as storehouses for the release of catalytically active small fragments capable of exhibiting heterosite subtrate activation. Theoretically, metal clusters are intermediates between mononuclear complexes and metal surfaces, i.e., they serve as a bridge between molecular and solid-state chemistry. Transition metal clusters are ideal candidates to study M-M interactions stretching from the single bond to the collective metallic behavior found in a three-dimensional network of metal atoms. The reaction between the redox-active diphoshpine ligand bpcd and RU(CO) has been examined under a variety of conditions. The disubstituted cluster Ru3(CO)10(bpcd)(2) has been synthesized and shown to contain a chealating bpcd ligand, on the basis of IR and 31P NMR data. The cluster 2 (chelating isomer) undergoes cluster fragmentation at ambient temperatures in the dark to give the binuclear compound 3 and Ru3(CO)12, with no evidence for the formation of 4. Both 3 and 4 have been isolated and fully characterized in solution by IR and NMR spectroscopy, and the solid-state structure of each new binuclear compound has been established by X-ray diffraction analysis. Independent experiments reveal that dinuclear 3 is converted to 4 by 366 nm light with a quantum efficiency of .0364.

No description available.

Abstract: Pincer compounds are organometallic complexes with intriguing tunable reactivities. In this work we explore their unique properties and reactivities through spectroscopic and computational investigations, with a focus on the PN3P pincer platform. First, we conducted a computational study on five pincer complexes with stereogenic phosphine arms that have multiple well-defined rotamers. Significant energy differences could be found between the lowest and highest energy rotamer in each set of pincer complexes. All rotamers for reactant, transition state, and product, were evaluated in a reaction energy profile of a CO2 reduction by a pincer nickel hydride, and we found that this reaction could be found either favorable or unfavorable, depending on the choice of rotamer. A software to generate rotamers has been developed and applied to the work presented in this part. The zwitterionic aromatic resonance form has a large contribution in the dearomatized PN3P* nickel pincer complexes, which is demonstrated by the imine arm's ability to act as an organic σ-donor, similar to NHC catalysts. Related to this property, as well as the pincer compound's ability to undergo metal-ligand cooperation catalysis, is the basicity (or acidity) of pincer ligand spacer arms. Therefore, we have determined the Brønsted basicity of the imine arm in three PN3P* nickel pincer complexes in THF. The relative basicity was found to be strongly influenced by the X ligand trans to the PN3P* ligand, and less by alkyl groups on phosphine donor arms. Finally, we explored the reactivity between a PN3P* rhodium carbonyl pincer complex and dioxygen at room temperature in solution, and at elevated temperature in the solid state. Intriguingly, the singlet PN3P* rhodium carbonyl complex reacts with the triplet dioxygen both in solution and in the solid state to afford oxidation on the ligand backbone. This is possible due to the ligands ability to do a single-electron transfer to dioxygen. The solid state reaction was studied with in situ rhodium K-edge X-ray absorption spectroscopy under dioxygen flow, where an isobestic point was observed, and simulation studies support formation of a Rh-O2 adduct. In situ FTIR studies in a static dioxygen environment revealed that the PN3P* rhodium carbonyl complex is able to facilitate the incorporation of O2 into CO and CO2.

Oxidative stress plays an important role in cardiac diseases, which has been well demonstrated, whereas the role of reductive stress has been poorly investigated. We and others have shown previously that heat shock protein 27 (Hsp27) plays a role as an antioxidant. To investigate whether overexpression of Hsp27 could lead to reductive stress and result in cardiomyopathy, we generated transgenic mice with different expression levels of Hsp27. We observed that transgenic mice with high levels of Hsp27 developed cardiomyopathy. The myopathic hearts were under reductive stress, which was evidenced by an increased ratio of reduced glutathione/oxidized glutathione and a decreased level of reactive oxygen species. In addition, upregulated glutathione peroxidase 1 and decreased iron content were revealed in the myopathic hearts. More importantly, inhibition of glutathione peroxidase 1 significantly attenuated the development of cardiomyopathy. The data indicate that the Hsp27-induced cardiomyopathy could be attributed to, at least in part, upregulation of glutathione peroxidase 1. Our findings suggest that reductive stress plays an important role in the development of cardiomyopathy and that Hsp27 may serve as a potential target for the treatment of patients with cardiomyopathy.

Indiana University-Purdue University Indianapolis (IUPUI) / Colonial settlement of Indiana changed the environment in significant ways; the aim of this study is to quantify the impacts of settlement through the use of geochemical proxies including: % lithics; the carbon (δ13C), nitrogen (δ15N), and sulfur (δ34S) isotope composition of organic matter; the elemental composition of carbon (TOC) and nitrogen (Ntot) in organic matter and their ratio (C/N); the δ34S of mineral sulfides (pyrite and acid volatile sulfides); and iron redox proxies. Lakes are a great recorder of aquatic-terrestrial linkages on both local and global scales. Martin lake’s watershed, in northeastern Indiana, was settled in 1840 by Euro-Americans, and since then clear shifts in lake chemistry are recorded in its sediments. A core spanning roughly the last 300 years taken from Martin Lake is the basis of this study. The impacts of settlement can be seen through the lenses of all the proxies that were used in this study. 1) Post-settlement deforestation increased erosion in Martin Lake’s watershed, increasing sedimentation rates and % lithics. 2) δ13C of organic matter reveals a pattern of deforestation and partial regrowth and agricultural use of land. 3) A pronounced increase in δ15N timed with the change in population at the time of settlement is consistent with the increased input of human or animal waste into Martin Lake. 4) TOC and C/N show an overall increase in the amount of organic matter within the lake caused by deforestation, and that the increased nutrient supply may have stimulated more in-lake productivity. 5) δ34S of mineral sulfides show that deforestation lead to an increase in the available sulfate pool of Martin Lake, which in combination with 6) an increase in FeHR created redox conditions in which pyrite formation was more favorable. These factors culminated in a transition in Martin Lake chemistry and redox cycling within the sediments.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18952号 / 工博第3994号 / 新制||工||1615(附属図書館) / 31903 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 北川 進, 教授 杉野目 道紀, 教授 宮原 稔 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20935号 / 理博第4387号 / 新制||理||1630(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 時任 宣博, 教授 大須賀 篤弘, 教授 依光 英樹 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Selenoprotein H (SELENOH) is a nucleolar oxidoreductase with DNA binding properties whose function is not well understood. To determine the functional and physiological roles of SELENOH, a knockout of SELENOH was generated in cell lines using CRISPR/Cas9-mediated genomic deletion and in mice by targeted disruption. Based on the sequenced genome, the results of deduced protein sequences indicated various forms of mutants in the CRISPR/Cas9-mediated knockout, including a frame-shift by aberrant splicing and truncated SELENOH by early termination of the translation process. Loss of SELENOH in HeLa cells induced slow cell proliferation, the formation of giant multinucleated cells, accumulation of unrepaired DNA damage and oxidative stress, and cellular senescence. SELENOH cells were enlarged and possessed a single large nucleolus. Atomic force microscope showed increased stiffness in the nucleoli of SELENOH knockout cells, which suggests that SELENOH maintains the flexible structure of the nucleolus. Furthermore, the knockout of SELENOH led to a large-scale reorganization of the nucleolar architecture with the movement of nucleolar protein into nucleolar cap regions in response to oxidative stress. The nucleolar reorganization is dependent on ATM signaling. Altogether, results suggest that SELENOH appears to be a sensor of oxidative stress that plays critical roles in redox regulation and genome maintenance within the nucleolus. To determine the physiological role of SELENOH in vivo, Selenoh knockout mice were generated by targeted deletion through homologous recombination. Selenoh+/− mice were fertile and phenotypically indistinguishable from wild-type littermates. Results from matings of Selenoh+/− mice showed a significantly reduced fraction of Selenoh−/− offspring on the basis of Mendelian segregation. Since some Selenoh−/− were born, it is likely that Selenoh is a partially essential gene in mice. Live-born Selenoh−/− mice were viable and born without apparent phenotypes. Selenoh−/− mice at 2-month of age showed increased GPX activity in the lung but not in the brain and liver. Furthermore, loss of Selenoh resulted in the aggravated formation of aberrant crypt foci in the colon of Selenoh+/− mice that were injected with azoxymethane. Altogether, SELENOH has critical roles in embryogenesis and colorectal carcinogenesis.