New fields in organic chemistry: Developments in aqueous organoindium chemistry and ring closing olefin metathesis

Mendez-Andino, Jose Luis The Ohio State University 2001 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Organoindium chemistry is an area that has elicited considerable interest recently because it has been found that selected processes can be performed in aqueous media efficiently. These findings have caused a major impact in the quest for alternative synthetic pathways for pollution prevention. Similarly, the discovery of new reagents to perform ring closing metathesis reactions has received enormous attention in recent years. Grubbs' catalyst is the reagent that has revolutionized this area and provided the organic chemist with a powerful new synthetic tool. Novel methodologies in the areas of organoindium chemistry and ring closing olefin metathesis have been responsible for significant advances in synthetic chemistry in recent years. Our goal was therefore to merge the fields of aqueous organoindium chemistry and ring-closing olefin metathesis (RCM) to develop methodologies with application in synthetic organic chemistry. Initially, we examined the stereochemical course of the intramolecular cyclization of allylic bromides with indium metal in water. Proper comparison with the fluoride ion-promoted ring closure of allylsilanes in organic media was made. The second stage of this work consisted in developing a general procedure for the synthesis of α-methylene lactones fused to larger rings. The convenient approach originates with two ω-unsaturated aldehydes of the same or different chain length. Organoindium chemistry and ring closing olefin metathesis were employed to develop the convergent strategy for the synthesis of α-methylene-γ-lactones fused to medium and large carbocyclic ring systems. We also targeted for investigation a convenient method for achieving four-carbon intercalations between the carbonyl groups of α-diketones. A three-step sequence consisting of indium-promoted diallylation, ring-closing metathesis, and oxidative diol cleavage with lead tetraacetate lends itself conveniently to useful structural modifications. Finally, we investigated the synthesis of an homologous series of bicyclo[1.1.1]pentane-1,3-dicarboxylate esters featuring ω-alkenols of differing chain length. Their ability to undergo ring closing metathesis/paddlane formation in the presence of Grubbs' catalyst was studied in detail.

Gas-phase covalent and non-covalent ion/ion chemistry of biological macromolecules

Stutzman, John R Purdue University 2013 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Gas-phase ion/ion chemistry involves the interaction of oppositely charged ions inside of the mass spectrometer. During this gas-phase chemistry, particle transfer (i.e., proton and electron) or synthesis can occur at rapid reaction rates. Particle transfer represents a mature area of ion/ion chemistry, while selective covalent modification represents a fairly new area of gas-phase chemistry. Gas-phase covalent chemistry is based on traditional solution phase organic chemistry. The work demonstrated in this dissertation greatly involves gas-phase covalent and non-covalent Schiff base chemistry on peptide and protein ions. The reagent dianion, 4-formyl 1,3-benzene disulfonic acid, has been used to covalently modify unprotonated primary amines present in peptide and protein ions. In addition, strong non-covalent interactions have also been observed with arginine-containing peptides ions. Studies of their dissociation behavior as well as the nature of their interaction (i.e., covalent versus non-covalent) have been investigated. Application of this Schiff base ion/ion chemistry has been demonstrated on matrix assisted laser desorption/ionization (MALDI)-derived peptide ions. Such Schiff base ion/ion chemistry, whether electrospray or MALDI-derived, can produce complementary or even an increase in structural information. Multiple covalent modifications within one ion/ion encounter have been demonstrated on peptide and protein cations via Schiff base cluster anions. This dissertation also highlights the gas-phase transformation of phosphatidylcholine cations into demethylated phosphatidylcholine anions, which provides an increase in structural information upon activation. As a whole, gas-phase covalent and non-covalent ion/ion chemistry represents a promising new area for identifying and characterizing biological analytes.

Learning the language of organic chemistry: How do students develop reaction mechanism problem-solving skills?

Anderson, Jason P Purdue University 2009 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Reaction mechanisms and the associated electron-pushing formalism are a symbolic language used by practicing organic chemists to navigate problems common to organic chemistry. Although the importance of this mechanistic language has been noted by practitioners and educators alike, it is often misunderstood and poorly applied by students and novice organic chemists. It was the disconnection between student and practitioner that was at the center of this research. The goal of this study was to determine how organic chemistry graduate students' mechanistic problem-solving strategies developed as they became members of the organic chemistry research community. This process was explored in eleven organic chemistry graduate students by investigating the participants' interaction with: their dissertation research projects, weekly mechanism meetings held by organic chemistry research groups, and a variety of activities that were dependent on their year in graduate school. These activities included: advanced organic chemistry coursework and projects, original proposals (OP), the senior research seminar, and the process by which they defend their dissertation and search for a job. This study was designed and analyzed using a constructivist framework that was supplemented with situated learning perspectives (i.e. communities of practice). The data collected -- interviews, observations, artifacts, and field notes -- were then analyzed through an ethnomethodological lens. The results of this study indicated that the participants' overall developmental changes occurred as a result of acculturation in the organic chemistry community of practice. Furthermore, it was the authentic and active problem-solving efforts in the activities inherent to this community that provided the participants with a sense of ownership and membership within this community of practice through legitimate participation in these activities. It was apparent that the participants' interactions with this community -- through the research literature, their group members, research advisors, and course instructors -- were also essential to their development in general. This interaction and the participants' research problem-solving efforts resulted in a significant developmental shift in the usefulness of mechanisms. Finally, a theme that unified all of the participants in this study was their use of mechanisms to troubleshoot unexpected problems both in coursework and research.

Part I: The effects of laboratory curriculum and instruction on undergraduate students' understanding of chemistry. Part II: Raman spectroscopy studies of the synthesis of cuprates in molten hydroxide fluxes

Rickey, Dawn Kerry University of California, Berkeley 1999 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

<italic>Part I</italic>: <italic>The Effects of Laboratory Curriculum and Instruction on Undergraduate Students' Understanding of Chemistry</italic>. Shallow learning, that is, acquiring factual and procedural knowledge without a deeper understanding of the underlying ideas, is a typical result of science courses taught via the standard modes of lecture and follow-the-recipe laboratory experiments. To address the problem of shallow learning in general chemistry, my colleagues and I developed, implemented, and assessed a new laboratory program. The design of the curriculum and instruction for the MORE laboratory course was based on research in cognitive science and education. We also developed a new instructional tool, the Model-Observe-Reflect-Explain (MORE) Thinking Frame, to support our curricular and instructional goals. The MORE laboratory curriculum and instruction was tested in two laboratory sections selected at random from the general chemistry course, and was assessed in comparison with two matched Control sections participating in the standard laboratory curriculum. Analysis of the data revealed a consistent picture of students enrolled in the MORE laboratory course developing significantly enhanced metacognitive abilities, understanding of the fundamental chemistry ideas studied in the general chemistry course, and abilities to solve near transfer and isomorphic examination problems compared with the Control group. The design of the Model-Observe-Reflect-Explain (MORE) laboratory instruction around our three principles encouraged and supported students' development of skills for reflection upon and revision of their understanding of the basic chemistry ideas studied in the laboratory, resulting in improved learning and problem-solving. <italic>Part II</italic>. <italic>Raman spectroscopy studies of the synthesis of cuprates in Molten Hydroxide Fluxes</italic>. The goal of the research presented here was to refine the model of cuprate synthesis in alkali metal hydroxide melts by using Raman spectroscopy to directly determine the oxo and metal-oxo solution species present in hydroxide melts under particular reaction conditions. The Raman spectroscopy studies described in this thesis were successful at contributing to an improved understanding of the behavior of copper in molten hydroxide solutions. In addition, the Raman spectra provide the first direct evidence of the existence of a stable Cu<super>3+</super> species in molten hydroxides solutions open to the air at temperatures above about 400°C. One key finding of the Raman spectroscopy studies was that, contrary to what was previously postulated, Cu<super>3+</super> was found to be more stable in dry, highly oxidizing melt conditions at high temperatures than it is in melts of intermediate dryness and temperature. (Abstract shortened by UMI.).

Study of reductions using flow chemistry and catalytic hydroboration of alkenes and alkynes with potassium carbonate(cat.)

Kim Taesung 강원대학교 대학원 2019 국내석사

<Part I> Due to its high contact efficiency and heat capacity, the flow reactions under micro reactor is known to be highly efficient and reactive than conventional batch systems. Using flow system, with low catalyst load and shorter reaction time an organic reaction can operate with excellent yield. As a result numerous chemical transformations which otherwise difficult to produce in conventional methods were reported by various academies and institutes. As part of our search for efficient reducing agents and selective reductions, and in view of flow technique importance, we made efforts for partial reductions and hydroboration reactions under flow chemistry with ester group. Accordingly, an ester group was reduced with LiOtBu, DIBALH (through the in-situ generated LDBBA), and LiOtBu, MeLi catalyzed hydroboration with pinacolborane. <Part II> The importance of green protocols under the environmental concern, cost reduction and simplify of procedures has dawn great attention in recent years. In addition, increased efficacy of the reaction also expected due to the intimacy of the reagents and catalysts used. In this regard, catalytic reactions under minimal solvent or solvent free conditions are becoming most valuable choices in research. The hydroboration of unsaturated hydrocarbons provides useful synthons for cross-coupling and other important functional transformations. The hydroboration of unsaturated bonds with sodium borohydride-aluminum chloride was first reported by Nobel laureate Prof. H. C. Brown. Later, efforts have been made by several authors to find efficient catalytic system for unsaturated hydroboration (C-C and C=X; X = O, NH). As a result number of catalytic systems including transition metal complexes, main group-alkaline earth metals, and lanthanide complexes were reported. In the present study, we have taken up the research on transition metal free hydroboration of alkenes and alkynes using lower active reductant such as pinacolborane (HBpin) catalyzed by inexpensive and mild base K2CO3. Accordingly a 1-5 mol% K2CO3 could efficiently provided hydroboration in good yields under solvent free condition. Flow chemistry란 반응물을 반응기 내부로 주입시켜 연속적인 흐름을 통해 반응하는 방식이다. 반응기로는 micro reactors가 이용되기도 하는데 부피 대비 표면적이 높은 장점이 있어 열전달 효율 등이 높다. 이러한 장점을 토대로 DIBALH와 lithium tert-butoxide를 이용한 esters의 부분환원 및 methyl lithium 또는 lithium tert-butoxide를 촉매로 이용한 esters의 촉매 수소화 붕소 첨가반응을 flow chemistry에 적용하여 본 결과 batch system 보다 LDBBA의 합성에 효과적임을 알 수 있었다. 그러나 esters의 부분환원 및 촉매 수소화 붕소 첨가반응에서는 기존의 batch system과 비교하여 뚜렷한 장점을 찾을 수 없었다. 수소화 붕소 첨가반응은 유기합성에 중요한 반응으로 최근에는 다양한 촉매를 이용한 촉매 수소화 붕소 첨가반응이 연구되고 있다. 현재까지 불포화 탄화수소의 촉매 수소화 붕소 첨가 반응에 보고된 촉매들은 대부분 비교적 고가의 전이금속을 포함하거나 보관 및 사용이 어려운 강한 친핵성 및 염기성의 시약이 대부분이다. 이와 같은 문제점을 해결하고 보다 효과적인 불포화 탄화수소의 촉매 수소화 붕소 첨가반응을 진행하기 위해 새로운 촉매로 potassium carbonate를 적용시켜 본 결과 알켄으로부터 상응하는 alkyl boronic esters를 알카인의 경우에도 상응하는 vinyl boronic esters를 성공적으로 합성 할 수 있었다.

Understanding Atmospheric Aerosol Dynamics and Condensed-Phase Chemistry via Laboratory-Based Aerosol Mass Spectrometry (AMS)

Niedek, Christopher University of California, Davis ProQuest Dissertat 2025 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Organic aerosols, and atmospheric condensed phases more broadly, are important components of the troposphere. Despite a large amount of effort over the past few decades to better understand the dynamic chemistry of ambient aerosols, our knowledge of the characterization and fate atmospheric condensed-phase species remains limited. A critically understudied aspect of this chemistry is the chemical processes occurring in aqueous particles and aerosol liquid water (ALW). A more thorough characterization of the chemical composition and processes of these atmospheric condensed phases is necessary to improve the accuracy of models of aerosol impacts on climate change and human health. This dissertation focuses on developing novel methodologies for the study of atmospheric condensed phases and applying these techniques to understand the aqueous-phase chemistry of phenols and furans (both important biomass burning (BB) emission species) under more ALW-like conditions and to examine vertical distributions in ambient aerosol chemistry.Chapter 2 presents a unique application of lab-based, analytical aerosol chemistry techniques to evaluate the ability of purported "aerosol barriers" to retain aerosols in a hospital setting. Shortly after the start of the COVID-19 pandemic, there was interest in the use of various types of barrier devices to protect hospital staff from potentially infectious respiratory aerosols during aerosol generating procedures (e.g. intubation). However, very little data existed on the ability of these types of devices to retain aerosols and therefore protect the user. A novel methodology involving simultaneous, real-time analysis of modeled, exhaled particles using an aerosol mass spectrometer (AMS) and condensation particle counter (CPC) was developed to evaluate the aerosol retention characteristics of barrier devices. Aerosol retention was largely dependent on the degree of enclosure of the barrier device. A barrier device that fully encloses a patient can effectively retain respiratory aerosols, while aerosols could be detected leaking from any available opening. Additionally, aerosol evacuation can be performed to reduce the internal aerosol count to near-background levels.Chapter 3 details the development of a micronebulization aerosol mass spectrometry (MN-AMS) technique for analysis of low volume, low dissolved mass extracts of particulate matter (PM) collected on filters. Limitations on standard filter extraction and aerosol generation techniques require long filter collection times and prohibit the use of advanced PM collection strategies like uncrewed aerial systems (UAS). The MN-AMS technique can generate aerosols suitable for AMS analysis from microliter volumes of liquid filter extracts containing nanograms of dissolved PM, a significant improvement over standard aerosol generation techniques. This technique was evaluated against standard aerosol generation techniques with the AMS and ion chromatography and was able to accurately reproduce expected aerosol chemical compositions across a range of solution volumes. Then, samples collected on the ground and aboard a UAS at the Southern Great Plains (SGP) atmospheric observatory Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) user facility were analyzed using MN-AMS. This technique accurately reproduced the expected aerosol chemical compositions and mass concentrations ascertained by on-the-ground measurements performed by an aerosol chemical speciation monitor (ACSM). Chapter 4 further demonstrates the MN-AMS technique by examining the detailed chemistry of a set of filter samples collected using the ARM UAS named the ArcticShark during a set of flight campaigns performed in March, June, and August of 2023. On-board measurements of ambient RH, temperature, wind speed and direction, and cloud droplet concentrations were combined with ground-based measurements of cloud-base heights and planetary boundary layer heights (PLBH) to better understand aerosol chemistry at SGP both at ground level and aloft. Chemistry measured at altitude was compared to a ground-level ACSM. The two measurements were most similar when the PBLH was high and the ArcticShark was sampling well below it. When the ArcticShark had significant sampling time above the PBL, measurements of PM chemistry diverged from those measured on the ground. Additionally, seasonal insights into PM chemistry at SGP, including seasonal variations in organic nitrogen species, were discussed. Both the speciation and average oxidation state of organic nitrogen species changes from March and June to August. Last, positive matrix factorization (PMF) was applied to the UAS samples on a monthly basis. In each month, factors similar to oxidized organic aerosols (OOA) were found. In March and June, a factor was found that correlated to specific samples that were largely from above the PBL and resembled highly oxidized (relative to the rest of the monthly samples) OA that was chemically distinct from PM measured during the other sampling days in March and June.In Chapter 5, a novel photoreaction system named the small pathlength photoreactor (SPP) is described. The SPP was designed to study condensed-phase photochemistry at conditions similar to those found in ALW. General characterization of the SPP was performed, including RH and temperature control within the reaction chamber and comparison of model reactions of phenol and furan photochemistry performed in more established photoreaction systems. Photochemistry under ALW conditions was exemplified by examining guaiacyl acetone (GA), a model BB phenol, and 3,4-dimethoxybenzaldehyde (DMB), a model triplet carbon photosensitizer, photochemistry under high organic concentrations and high salt concentrations. High concentrations of light absorbing organics can cause issues with light screening under typical photochemical setups where pathlengths are on the order of 1 cm. GA decay rates are notably increased as DMB concentrations increase, even despite light screening caused by increased GA concentrations, and high salt concentrations cause a slight decrease in GA decay rates. Similarly, the rate of GA oligomerization is increased under high organic concentrations and decreased under high salt conditions. Secondary organic aerosol yields are generally decreased under ALW conditions.In Chapter 6, the SPP is further utilized to examine furan-singlet oxygen (1O2) under high ionic strength conditions. Like phenols, furans can be significant components of BB emissions. Singlet oxygen chemistry has been explored in environmental waters, and under low salt concentration (<2 M) conditions, but almost no data exists on 1O2 chemistry under ALW conditions where ionic strengths can reach as high as 20 M, at least an order of magnitude higher than what has been studied prior. For reactions of FFA and 1O2 (generated from rose Bengal (RB), a common 1O2 photosensitizer), a moderate correlation between photosensitizer absorption area and FFA decay rate was found. This suggests that ionic strength is modifying the 1O2 steady-state concentration of the system, as opposed to second order rate constants between furans and 1O2. The effects of ionic strength on the furan-1O2 were also explored more broadly by examining the decay rates of a set of furans using different 1O2 photosensitizers and salts. Similar to what has been shown in the literature under low ionic strength conditions, ionic strength effects on 1O2 photochemistry are highly dependent on salt concentration, salt identity, 1O2 photosensitizer identity, and to a lesser extent the identity of the furan. Singlet oxygen photosensitizer identity seems to be the largest contributor, where different photosensitizers exist in different regimes of salt effects on furan-1O2 chemistry.

Development and Application of Coupled Atmospheric Chemistry Models

Lin, Haipeng Harvard University ProQuest Dissertations & Theses 2024 해외박사(DDOD)

소속기관이 구독 중이 아닌 경우 오후 4시부터 익일 오전 9시까지 원문보기가 가능합니다.

Comprehensive and accurate representation of atmospheric chemistry in Earth System Models is a major priority in geoscientific modeling. GEOS-Chem is a state-of-the-science atmospheric chemistry model used by hundreds of research groups worldwide. It has been restructured to operate as a chemical module in weather and climate models while sharing the same scientific codebase as the standalone chemical transport model. The Community Earth System Model version 2 (CESM2) is a state-of-science Earth System Model that has participated in multiple model intercomparison activities. CESM2 includes a comprehensive chemistry option, CAM-chem, with a different development heritage from GEOS-Chem. The two models show large differences in model skill in comparison to observations in different regions, implying differences in sensitivity to perturbations. Previous model intercomparisons generally compared entire modeling systems, introducing first-order differences complicating the attribution of particular strengths in reproducing observations to specific representations of processes in each model. Implementation of GEOS-Chem within CESM2 as an alternative chemistry option to CAM-chem allows for detailed process-based intercomparison between two models, informing more accurate representation of atmospheric chemistry, and contributing to the vision of a modular chemistry-climate model.In this work, we develop a multi-model emissions and data tool through an updated version of the Harmonized Emissions Component (HEMCO) and couple it to the CESM2 model. This serves as the foundation for implementation of GEOS-Chem within CESM2 and intercomparison with CAM-chem (Chapter 1). Because of the increasing chemical complexity in atmospheric chemistry models resulting in increased computational burden, which is particularly relevant in coupled model environments, we develop an adaptive, auto-reduction solver for chemical kinetics that can reduce the complexity of the chemical mechanism depending on local conditions. It can provide a ∼30% speed-up in the chemical solver while introducing ∼1% error in the troposphere. We evaluate the adaptive solver in the offline GEOS-Chem chemical transport model at a 2◦ x 2.5◦ resolution, but it has been implemented in the Kinetic Pre-Processor (KPP) software package making it easily extensible beyond GEOS-Chem (Chapter 2). We then apply the coupled chemistry-climate model GEOS-Chem within CESM2 to compare its representation of tropospheric oxidant chemistry against the default CAM-chem chemistry driven by the same dynamics, physics, and emissions. We use ozonesondes and aircraft observations from the ATom-1 and KORUS-AQ campaigns to identify and attribute major differences between the two models. (Chapter 3).

An In Situ Click Chemistry Strategy Using a DNA-Encoded Library for the Discovery of Highly Potent and Selective Protein Ligands

김민경 포항공과대학교 일반대학원 2026 국내박사

Capture agents that selectively bind to biological targets are indispensable tools in diagnostics, therapeutics, and biomedical research. However, discovering such capture agents, particularly for structurally conserved or challenging targets, remains a challenge. Here, we describe a protein-templated in situ click strategy enabled by a nanoparticle- based DNA-encoded library (nanoDEL) platform. The nanoDEL enables the construction and screening of vastly large, chemically diverse combinatorial libraries with high redundancy, far exceeding the scale and throughput of conventional approaches, such as one-bead-one- compound and solution-phase in situ click methods. Thus, this enables the rapid and efficient identification of high-affinity, high-selectivity ligands in a single selection round, eliminating the need for iterative screening. In this thesis, we describe the development of a novel in situ click chemistry screening strategy based on nanoparticle-supported DNA-encoded library (nanoDEL) technology. In, the current state and recent advances in in situ click chemistry screening methods are reviewed, with particular emphasis on their inherent limitations and the need for innovative strategies to improve screening efficiency (Chapter I). Secondly, we present preliminary study results related to a screening approach capable of targeting both the active site and peripheral site of the target protein using nanoDEL technology (Chapter II). Third of all, we introduce a new screening platform that integrates nanoDEL technology with in situ click chemistry, enabling the efficient and selective discovery of ligands targeting phosphatases (Chapter III). In Chapter I, the background and overview of this thesis are provided to highlight the current limitations of existing technologies and the rationale for developing a new screening strategy. The current state of in situ click chemistry screening methods and their associated shortcomings are reviewed. In addition, the recently developed nanoDEL technology from our lab, which effectively overcomes the limitations of conventional DEL approaches, is introduced, followed by a brief summary of the overall research strategies and objectives presented in this thesis. In Chapter II, the preliminary study is reported : a nanoparticle-based DNA-encoded peptoid library was constructed to identify ligands targeting both the catalytic and peripheral sites of protein tyrosine phosphatase 1B (PTP1B). A phosphotyrosine-mimetic anchor was employed as the core recognition element, while peptoid fragments were incorporated to mimic substrate-adjacent interactions. The library was synthesized on nanoparticle and screened against PTP1B using affinity selection and next-generation sequencing analysis. Although the screening demonstrated the feasibility of nanoparticle-based combinatorial ligand discovery, the identified compounds exhibited only weak inhibitory activity (IC₅₀ = 30–90 μM). Analysis revealed that internal placement of the azide moiety limited productive binding orientations, and the absence of a protein-templated bond formation mechanism hindered efficient ligand assembly. These findings underscored the need for a more effective strategy to promote site-directed ligand formation. Consequently, in the following chapter, an in situ click chemistry–based screening platform is introduced, featuring terminally positioned azide functionalities to enhance reactive accessibility and enable protein-guided assembly of high-affinity PTP1B ligands. In Chapter III, the development of novel in situ click chemistry screening methods using nanoDEL is reported. As described in Chapter I-II, the use of nanoparticles as solid supports for the construction of DNA-encoded libraries provides an effective strategy to overcome the limitations of conventional in situ click chemistry screening methods. In this work, we introduced a new screening strategy that integrates nanoDEL technology with protein-templated in situ click chemistry. This hybrid approach leverages the high-throughput capabilities of nanoDEL and the selectivity provided by in situ click chemistry, offering a new framework for efficient and selective ligand discovery. To demonstrate the utility of this approach, we performed an in situ click chemistry screening of a 27-million-member nanoDEL composed of azido-functionalized peptoids in the presence of a weakly binding, promiscuous alkyne-bearing anchor ligand. Remarkably, a single round of in situ click screening yielded bidentate inhibitors of PTP1B, a therapeutically relevant yet challenging target due to its highly conserved active site among phosphatase family members. The identified inhibitors exhibited nanomolar potency and exceptional selectivity over closely related phosphatases, validating the ability of the nanoDEL platform to discriminate among structurally similar enzyme isoforms. Structural and biochemical analyses confirmed the formation of a triazole-linked bidentate binding mode and revealed key interaction hotspots responsible for the enhanced affinity and selectivity. Furthermore, cellular studies demonstrated that the lead ligands effectively modulated PTP1B activity in relevant cancer cell models with minimal off-target effects. Overall, this work represents a broadly applicable strategy for discovering high-performance capture agents, particularly for selectively targeting closely related protein families or isoforms where achieving selectivity remains a critical challenge. We expect that the nanoDEL-enabled in situ click chemistry approach would serve as a powerful and broadly applicable strategy for the discovery of high-affinity, high-selectivity capture agents.

Synthesis and Evaluation of Novel Radiotracers using Click Chemistry : Click chemistry를 이용한 새로운 방사성추적자의 합성 및 평가

김동현 성균관대학교 일반대학원 2009 국내박사

It is important to develop novel compounds possessing potent biological activities for medical uses. However, synthesis of these compounds is generally slow, costly, and hindered by complex synthesis pathways. In this context, synthesis of novel radiopharmaceuticals is also a difficult task. Click chemistry known as Cu(I)-catalyzed 1,3-cycloaddition between terminal alkynes and azides has been shown to be a simple, regioselective and high yielding reaction for synthesis of various triazole compounds. In this study, therefore, we developed 4-[18F]fluoro-1-butyne, a synthon for click chemistry with azides, and applied it to development of novel positron emission tomography (PET) radiotracers, such as glucose, fatty acid, and cRGD peptide analogs. Radiolabeled glucose analogs are attractive probes for metabolic imaging. However, there are no suitable glucose radiotracers, except [18F]FDG. In this study, a 18F-labeled glucose analog, 4-[(2-[18F]fluoroethyl)-1-(β-D-glucopyranosyl)]-1H-1,2,3-triazole ([18F]1), was synthesized using click chemistry and evaluated in vitro. In terms of labeling, click chemistry was superior to conventional chemistry, due to a higher decay-corrected radiochemical yield (30% vs. 21%), higher specific activity (59.9 GBq/&micro;mol vs. 23.5 GBq/&micro;mol), and shorter synthesis time (75-80 min vs. 95-100 min). In vitro evaluation demonstrated that [18F]1 does not act as a hexokinase substrate and has low and non-specific uptake by SNU-C5 cells. These results suggest that click chemistry offers a rapid and efficient radiolabeling method which does not require the protection of functional groups, although a triazole moiety at C1 of [18F]1 is incompatible for hexokinase phosphorylation and facilitative diffusion via Glut-1. Fatty acids are substrates for energy metabolism in myocardium. Therefore, radiolabeled fatty acid analogs are useful for evaluation of fatty acid metabolism in myocardium. In this study, we synthesized 17-[4-(2-[18F]fluoroethyl)-1H-1,2,3-triazol-1-yl]-6-thia-heptadecanoic acid ([18F]6) for the evaluation of fatty acid metabolism. Radiotracer [18F]6 was synthesized in 20-26% decay-corrected yields from 17-azido-6-thia-heptadecanoic acid and 4-[18F]fluoro-1-butyne using click chemistry. The tissue distribution of [18F]6 in mice showed high radioactivity accumulation in heart (3.28 % ID/g at 10 min and 3.01 %ID/g at 60 min post-injection), a prolonged myocardial elimination half-life (> 60 min), and a maximal heart to blood uptake ratio at 5 min post-injection (6.49). Pretreatment with etomoxir, a carnitine palmitoyl transferase (CPT) I inhibitor reduced myocardial radioactivity uptake at 30 min post-injection by 53%. Analyses of heart tissue samples showed that most of the radioactivity was present in tissue pellet (62-63%). These results suggest that [18F]6 undergoes metabolic trapping via β-oxidation in myocardium, and thus, suggest that it has potential use as a PET radiotracer for the evaluation of myocardial fatty acid metabolism. The αvβ3 integrin is expressed on proliferating endothelial cells and tumor cells of various origin. We synthesized a 17-[4-(2-[18F]fluoroethyl)-1H-1,2,3-triazole-1-yl]-5-oxo-9,12,15-trioxa-6-azaheptadecano-E[c(RGDyK)]2 ([18F]22) for minitoring αvβ3 integrin expression on tumor cells. The precursor was synthesized by conjugating 17-azido-5-oxo-9,12,15-trioxa-6-azaheptadecanoyl-NHS ester with E[c(RGDyK)2]. Radiotracer [18F]22 was prepared from 17-azido-RGD dimer and 4-[18F]fluoro-1-butyne using click chemistry and purified by reverse phase HPLC. Decay-corrected radiochemical yield of [18F]22 was 12-16% and total synthesis time including HPLC purification was 70-75 min. 의약품 개발을 위하여 생활성을 가지는 새로운 화합물을 개발하는 것은 매우 중요한 과제이다. 하지만 생활성 물질을 개발하는 것은 비용, 많은 시간, 그리고 복잡한 합성경로로 인한 많은 문제들을 포함하고 있다. 같은 맥락으로, 핵의학 진단을 목적으로 한 방사성의약품들은 동시에 병소에 특이적인 성질을 지녀야 하므로 새로운 방사성의약품의 개발은 매우 어려운 일이다. Click chemistry는 반응이 위치선택적이며 생성물의 수율이 높고 일반적으로 보호기의 관여가 없는 장점을 가지고 있어서 다양한 종류의 트리아졸 화합물을 합성할 수 있다. 이 연구에서는 아자이드 화합물과의 click chemistry를 위한 synthon으로4-[18F]fluoro-1-butyne을 개발하였으며, 이 방사성 알킨을 이용하여 새로운 방사성추적자들(글루코스, 지방산, RGD 펩타이드 유사체)을 합성하고 생물학적 유용성을 평가하였다. 방사성동위원소로 표지된 글루코스 유사체는 대사영상에 사용되는 방사성추적자이다. 이 연구에서는 click chemistry를 이용하여 4-[(2-[18F]fluoroethyl)-1-(β-D-glucopyranosyl)]-1H-1,2,3-triazole ([18F]1)를 합성하고 체외 평가를 수행하였다. 새로운 방사성추적자인 글루코스 유사체는 두 가지 방법으로 합성하였다. 토실레이트 전구물질을 사용하는 고전적인 표지방법과 click chemistry 방법을 이용하였다. 방사화학적 수율 및 비방사능 측면에서 후자의 방법이 우세하였으며 합성시간도 15분을 단축할 수 있었다. 이 결과는 [18F]1의 1번 탄소 위치에 트리아졸기가 치환되면 헥소키나제 인산화 및 Glut-1을 이용한 운반에 적합하지 않지만, click chemistry가 기능기의 보호가 필요하지 않은 빠르고 효율적인 표지방법이라는 것을 보여주었다. 지방산은 심근에서 에너지 대사를 위한 주요한 기질이다. 이 연구에서는 지방산 유사체로서 17-[4-(2-[18F]fluoroethyl)-1H-1,2,3-triazol-1-yl]-6-thia-heptadecanoic acid ([18F]6)를 합성하였으며 심근에서 지방산 대사를 위한 방사성추적자로서의 가능성을 평가하였다. [18F]6은 click chemistry를 사용하여 17-azido 6-thia-heptadecanoic acid와 4-[18F]fluoro-1-butyne로부터 20-26%의 수율로 합성되었다. 마우스의 체내분포 결과 심장에서 높은 섭취를 보였고(주사 후 1분에 3.70 %ID/g, 10분에 3.28 % ID/g), 심장에서의 방사능 배출 반감기는 60분 이상 이었으며, 심장 대 혈액 섭취비는 5분에서 6.49이었다. 카르니틴 팔미토일 트란스퍼라제(CPT) I 억제제인 에토목시어를 전처리한 마우스에서 심근의 방사능 섭취가 주사 후 30분에 53% 감소하였다. 또한 심장 조직의 분석은 대부분의 방사능이 조직 추출 후 남은 잔여물에 존재하였다(62-63%). 이 결과는 [18F]6이 심근에서 베타-산화를 통하여 대사적으로 포집되었음을 제시한다. 그러므로 [18F]6은 심근의 지방산 대사의 평가를 위한 PET 방사성추적자로서 가능성을 보였다. αvβ3 인테그린은 종양으로부터 방출된 단백질이 혈관형성을 유도할 때 수용체 역할을 담당하는 단백질이다. Arg-Gly-Asp (RGD)를 포함하는 펩타이드는 이 수용체에 특이적으로 결합하는 화합물로 알려져 있다. 이 연구에서는 종양세포의 αvβ3 인테그린의 발현을 모니터링하기 위하여 click chemistry를 사용하여 17-azido-cRGD dimer와 4-[18F]fluoro-1-butyne로부터 17-[4-(2-[18F]fluoroethyl)-1H-1,2,3-triazole-1-yl]-5-oxo- 9,12,15-trioxa- 6-azahepta- decano-E[c(RGDyK)]2 ([18F]22)를 합성하였다. 18F-표지를 위한 전구물질은 E[c(RGDyK)2]에 17-azido-5-oxo-9,12,15-trioxa-6-azaheptadecanoyl-NHS ester를 접합하여 합성하였다. [18F]22의 방사화학적 수율은 12-16%이었으며 HPLC 정제를 포함한 총 합성시간은 70-75분이었다.

Influence of turbulent transport and chemistry on the distribution of H_(2)O_(2), CH_(3)OOH, and HCHO in the remote marine boundary layer

장원일 University of Rhode Island 2002 해외박사

This study is motivated by the discrepancies found between observational data, collected in the marine boundary layer (MBL) during several large scale field campaigns, and photochemical model simulations appropriate to these campaigns. In particular, for the principal chemical species (H_(2)O_(2), CH_(3)OOH, and HCHO) theory and measurement remain unresolved. The temporal and spatial distribution and behavior of these key species indicates they are subject to chemical and physical processes such as gas-phase chemistry, scavenging by seasalt particles, seasalt aerosol chemistry involving halogen species, air-sea gas exchange, and FT-MBL exchange. We hypothesize that the incorporation of these processes into a single model will resolve the discrepancies. A one-dimensional photochemical model is developed which contains all processes to test this concept. A series of model simulations were conducted with varied model chemistry and material boundary flux conditions. The observational data (collected in the equatorial MBL during the PEM-Tropics (B) field program) were compared with the model results. The results indicate that two processes; 1) the FT-to-MBL O_(2) transport and 2) dry deposition critically influence the abundance of the key species. The results show that gas-phase chemistry alone with rationalized flux conditions is capable of capturing the behavior of CH_(3)OOH and HCHO and other processes (scavenging by seasalt particles and seasalt aerosol chemistry involving halogen species) are found to be negligible under PEM-Tropics (B) conditions. The comparisons show general agreement between the observations and theory for O_(3), OH, CH_(3)OOH, HCHO, NO_(x), and SO_(2). There remain gaps in our understanding of other species such as H_(2)O_(2), CH_(3)OH, DMS, and total nitrate (HNO_(3) + NO_(3)^(-)).