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Stanford University Department of Chemistry

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Works: 317 works in 323 publications in 1 language and 407 library holdings
Roles: Researcher
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Most widely held works by Stanford University
Energy transfer processes in solar energy conversion. Progress report, January 1, 1988--December 31, 1988( )

1 edition published in 1988 in English and held by 5 WorldCat member libraries worldwide

The program involves the investigation of excitation transport and electron transfer in complex systems. In the area of electron transfer, we have been studying electron back transfer following donor-acceptor photoinduced electron transfer. We are addressing this problem both theoretically and experimentally. In the area of excitation transport, we have been examining transport in solid solutions, liquid solutions, and in clustered excitation transport systems. Again, we are pursuing both experimental and theoretical approaches. The problem of electron back transfer between photogenerated ions is of central importance in both artificial and biological solar energy conversion. Once an electron has been transferred from an optically excited donor to an acceptor, back transfer competes with the ability of the radical ions to go on to do useful chemistry. We are studying the back transfer process using picosecond transient grating experiments in conjunction with time resolved and steady state fluorescence quenching measurements. The transient grating experiments makes the back transfer process a direct experimental observable, while the fluorescence experiments allow the forward transfer to be examined. By combining the experiments, a complete picture emerges. 10 refs
Energy transfer processes in solar energy conversion. Progress report( )

1 edition published in 1989 in English and held by 5 WorldCat member libraries worldwide

We have made substantial progress in experimental and theoretical studies in two areas: Photoinduced donor to acceptor electron transfer followed by back transfer in random solutions; and electronic excitation transport in systems with complex inhomogeneous spatial geometries and inhomogeneous energy distributions. Through the development of accurate statistical mechanical theories, we have been able to relate dynamics in complex systems to experimental observables. We have then used the experimental observables, time resolved fluorescence depolarization and transient grating experiments, to examine well defined molecular systems. The agreement between theory and experiment is excellent. 11 refs
Energy transfer processes in solar energy conversion( )

1 edition published in 1986 in English and held by 5 WorldCat member libraries worldwide

By combining picosecond optical experiments and detailed statistical mechanics theory we continue to increase our understanding of the complex interplay of structure and dynamics in important energy transfer situations. A number of different types of problems will be focused on experimentally and theoretically. They are excitation transport among chromophores attached to finite size polymer coils; excitation transport among chromophores in monolayers, bilayers, and finite and infinite stacks of layers; excitation transport in large vesicle systems; and photoinduced electron transfer in glasses and liquids, focusing particularly on the back transfer of the electron from the photogenerated radical anion to the radical cation. 33 refs., 13 figs
Energy transfer processes in solar energy conversion. Progress report, March 1, 1991--February 29, 1992( )

1 edition published in 1992 in English and held by 5 WorldCat member libraries worldwide

During the past year, we have been working in three general areas: electronic excitation transport in clustered chromophore systems and other complex systems, photo-induced electron transfer and back transfer in liquid solutions in which diffusion and charge interactions are important, and the construction of a new two color dye laser system to enhance our experimental capability
Energy transfer processes in solar energy conversion( )

1 edition published in 1987 in English and held by 5 WorldCat member libraries worldwide

This program involves the experimental and theoretical study of optically induced electron transfer and electronic excitation transport in systems with complex structures. The focus is to obtain an understanding of the intimate interplay among intermolecular interactions, structure, and dynamics. A combination of picosecond transient grating experiments, time resolved fluorescence depolarization experiments, conventional optical spectroscopy, and statistical mechanical theory is being employed to elucidated fundamental aspects of processes which are important in the conversion of solar energy to usable forms of energy. We are continuing to address the very important problem of electron back transfer following optically induced donor to acceptor electron transfer. In a system in which there are donors (low concentration) and acceptors (high concentration) randomly distributed in solution, optical excitation of a donor can be followed by transfer of an electron to an acceptor. One electron transfer has occurred. there exists a ground state radical cation (D) near a ground state radical anion (A⁻). Since the thermodynamically stable state is neutral ground state D and A, back transfer will occur. The electron will back transfer from A⁻ to D to regenerate the neutral species. In liquid solution, back transfer competes with separation by diffusion. Separated ions are extremely reactive and can go on to do useful chemistry. 10 refs
Energy transfer processes in solar energy conversion( )

1 edition published in 1992 in English and held by 5 WorldCat member libraries worldwide

During the past year, we have been working in three general areas: electronic excitation transport in clustered chromophore systems and other complex systems, photo-induced electron transfer and back transfer in liquid solutions in which diffusion and charge interactions are important, and the construction of a new two color dye laser system to enhance our experimental capability
Energy transfer processes in solar energy conversion. Progress report, January 1, 1987--December 31, 1987( )

1 edition published in 1987 in English and held by 5 WorldCat member libraries worldwide

This program involves the experimental and theoretical study of optically induced electron transfer and electronic excitation transport in systems with complex structures. The focus is to obtain an understanding of the intimate interplay among intermolecular interactions, structure, and dynamics. A combination of picosecond transient grating experiments, time resolved fluorescence depolarization experiments, conventional optical spectroscopy, and statistical mechanical theory is being employed to elucidated fundamental aspects of processes which are important in the conversion of solar energy to usable forms of energy. We are continuing to address the very important problem of electron back transfer following optically induced donor to acceptor electron transfer. In a system in which there are donors (low concentration) and acceptors (high concentration) randomly distributed in solution, optical excitation of a donor can be followed by transfer of an electron to an acceptor. One electron transfer has occurred. there exists a ground state radical cation (D) near a ground state radical anion (A⁻). Since the thermodynamically stable state is neutral ground state D and A, back transfer will occur. The electron will back transfer from A⁻ to D to regenerate the neutral species. In liquid solution, back transfer competes with separation by diffusion. Separated ions are extremely reactive and can go on to do useful chemistry. 10 refs
Energy transfer processes in solar energy conversion( )

1 edition published in 1989 in English and held by 5 WorldCat member libraries worldwide

We have made substantial progress in experimental and theoretical studies in two areas: Photoinduced donor to acceptor electron transfer followed by back transfer in random solutions; and electronic excitation transport in systems with complex inhomogeneous spatial geometries and inhomogeneous energy distributions. Through the development of accurate statistical mechanical theories, we have been able to relate dynamics in complex systems to experimental observables. We have then used the experimental observables, time resolved fluorescence depolarization and transient grating experiments, to examine well defined molecular systems. The agreement between theory and experiment is excellent. 11 refs
Degenerate four-wave mixing as a diagnostic of plasma chemistry. Progress report, September 15, 1992--March 15, 1993( )

1 edition published in 1993 in English and held by 5 WorldCat member libraries worldwide

Degenerate four-wave mixing (DFWM) has been found suitable for in situ monitoring during plasma-enhanced chemical vapor deposition. DFWM has been used to monitor CH and C₂ during synthesis of diamond thin films. Analysis of CH rotational and vibrational spectra confirmed the temperature trend predicted by the 1-D model. For substrate temperature 1200 K and free-stream temperatures of 3500 and 4300 K, the 1-D simulations predicted boundary layer thicknesses consistent with observations. The species concentration change across the boundary layer is dramatic; at 2 mm from the surface, both CH and C₂ reach maximum concentration. It has been demonstrated that, using a conventional laser system, operating at visible wavelengths (low energies), DFWM is nonintrusive and can generate signals that are easily monitored
Energy transfer processes in solar energy conversion( )

1 edition published in 1988 in English and held by 5 WorldCat member libraries worldwide

The program involves the investigation of excitation transport and electron transfer in complex systems. In the area of electron transfer, we have been studying electron back transfer following donor-acceptor photoinduced electron transfer. We are addressing this problem both theoretically and experimentally. In the area of excitation transport, we have been examining transport in solid solutions, liquid solutions, and in clustered excitation transport systems. Again, we are pursuing both experimental and theoretical approaches. The problem of electron back transfer between photogenerated ions is of central importance in both artificial and biological solar energy conversion. Once an electron has been transferred from an optically excited donor to an acceptor, back transfer competes with the ability of the radical ions to go on to do useful chemistry. We are studying the back transfer process using picosecond transient grating experiments in conjunction with time resolved and steady state fluorescence quenching measurements. The transient grating experiments makes the back transfer process a direct experimental observable, while the fluorescence experiments allow the forward transfer to be examined. By combining the experiments, a complete picture emerges. 10 refs
Contributions by Stanford University( )

in English and held by 2 WorldCat member libraries worldwide

Contains reprints of articles published by members of the department
Precursor-directed biosynthesis of macrolide antibiotics by Colin James Bell Harvey( )

1 edition published in 2012 in English and held by 2 WorldCat member libraries worldwide

Macrolides have long been among the most widely used antibiotics. Despite this utility, development of new macrolides through traditional synthetic and semisynthetic approaches has been greatly hindered by the inherent structural complexity of these compounds. Precursor-directed biosynthesis is a technique which circumvents this difficulty by incorporating simple synthetic precursors into a biosynthetic pathway, allowing the bulk of the molecule to be constructed enzymatically. This dissertation describes the evolution and application of a system for the facile production of new macrolides through precursor-directed biosynthesis. The results of this work are the discovery of an unexpected macrolide structure-activity relationship and the ultimate discovery of a promising new lead for macrolide development
The design, synthesis, and evaluation of simplified, function-oriented analogs of the daphnane diterpene orthoesters and the laulimalides by Nathan Benjamin Cardin( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

In this work, a function-oriented array of simplified analogs of the daphnane diterpene orthoester class of natural products bearing palmitate, phenyl, or phenylacetyl orthoesters was synthesized starting from commerically available starting materials via a key late stage common diversification intermediate. These families of novel compounds were evaluated for both selective PKC activation and growth inhibition of K562 (myleogenous leukemia) cancer cells. While these analogs showed no growth inhibitory activity in K562 cells up to concentrations of 10 micromolar, they did display varying profiles of PKC activation. One analog in particular demonstrated the ability to activate and cause translocation of conventional PKC b1 and novel PKC d to the same extent as resiniferonol, a potent natural resiniferonoid. A second analog, however, was found to activate novel PKC d selectively over conventional PKC b1; surprisingly, resiniferonol did not share this selectivity profile. Because the simplified, functional analogs synthesized in this study were shown to activate PKC while having no growth inhibitory activity, these compounds should be further investigated for their potential as therapeutic leads for the treatment of diseases like Alzheimer's or Parkinson's, in which (selective) activation of PKC could serve a therapeutic purpose without being plagued by growth inhibitory pathways
Part I, unnatural thymidine analogs and shape mimics as substrates for human thymidine kinases ; Part II, fluorescent size-expanded DNA analogs as efficient substrates for a template-independent DNA polymerase. by Sarah King Jarchow-Choy( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

This thesis is composed of two separate studies involving unnatural nucleoside (DNA) analogs in two different types of enzymes: human thymidine kinases 1 and 2 and terminal deoxynucleotidyl transferase (TdT). The ability of two types of unnatural DNA analogs, nonpolar nucleoside analogs and expanded nucleoside analogs, to act as efficient substrates in enzymes will be described. Nonpolar nucleoside analogs lacking the ability to hydrogen bond were synthesized to systematically vary in size and shape, and then used to probe the ability of two types of human thymidine kinases (TK1 and TK2) to recognize and phosphorylate these analogs. The results establish that nucleoside recognition mechanisms for these two classes of thymidine kinase are very different. On the basis of this data, nonpolar nucleosides are likely to be active in the nucleotide salvage pathway in human cells, suggesting new designs for bioactive molecules. Another class of nucleoside analogs, expanded nucleoside (xDNA) analogs, maintain the ability to hydrogen-bond to their respective natural bases, but have enhanced pi-stacking due to their larger size, allowing the molecule to have greater stability in a DNA duplex, and unique fluorescent properties. It was found that terminal deoxynucleotidyl transferase (TdT), a template-independent DNA polymerase, can accept multiple xDNA nucleotide analogs as substrates with efficiencies close to that of natural nucleotides. In addition, the expanded adenine (xA) and cytosine (xC) analogs show a visible and spectral change in fluorescence when TdT incorporates multiple analogs. The ease of enzymatic synthesis of these analogs and their inherent fluorescence suggest their use in nucleic acid labeling and hybridization studies. The comparable efficiencies which nonpolar nucleoside analogs and xDNA nucleotide analogs have to natural bases in thymidine kinases and TdT give new information about the steric and electronic requirements of these enzymes, and will be useful for potential therapeutic and biotechnological applications
Using synthetic small molecules to probe the structure and function of voltage-gated ion channels by Justin David Litchfield( )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

Several methods of examining the structure and function of voltage-gated ion channels are described. The first part of this work involves synthetic small molecules based on the structure of (+)-saxitoxin, a marine neurotoxin. (+)-saxitoxin interacts with the pore of the voltage-gated sodium (NaV) channel to prevent the passage of ions. A scaffold was designed to be modular, synthetically facile, and contain the functionality that had been implicated in the previous literature. Several members of this family of molecules were produced, and they were assayed for occlusion of sodium current (INa). The second part of this work examines the gating kinetics of voltage-gated potassium (KV) channels. 6-bromo-mercaptotryptamine (BrMT) is a marine neurotoxin that has been shown to alter the gating kinetics of KV channels. Specifically, BrMT affects the early, typically independent steps of KV gating by stabilizing the resting state of some number of the subunits. A family of small molecules was designed and synthesized that would examine the functional effects of different parts of the BrMT molecule. BrMT is a dimer containing three key functional groups: a halogenated indole, a pendant ethyl-amine, and a disulfide linker. Variance at all these positions was examined, and each had different effects. Notably, one of the variants, in which the disulfide linker was substituted for an oxy-bismethyl ether linker, affects KV gating in a different way from BrMT. Alternate models of gating in the presence of this novel analog are discussed
Single-walled carbon nanotubes (SWNTs) as near infrared fluorescent imaging agents in biological systems by Kevin David Welsher( )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

The near infrared range has long been known to be advantageous for biological imaging and sensing applications. In particular, the second near infrared window (1000 nm -- 1400 nm, NIR II) is characterized by low endogenous autofluorescence and deep tissue penetration due to reduced tissue scatter. To address the dearth of fluorophores in this window, this work focuses on utilizing the intrinsic near infrared photoluminescence of semiconducting single walled carbon nanotubes (SWNTs) to take advantage of this unique spectral region. First, SWNTs are made bio-inert and applied as fluorescent probes for highly specific cellular targeting using antibodies such as Rituxan and Herceptin. These probes were then used for the first whole animal fluorescent imaging using SWNTs in vivo following tail vein injection, including the observation of high SWNT accumulation in tumors. By implementing a surfactant exchange method to improve the fluorescence yield of SWNTs solubilized by phospholipid-polyethylene glycol, high magnification intravital microscopy of tumor vessels beneath thick skin was achieved. Further improvements were made to improve the fluorescence yield of the SWNT probes by utilizing a density gradient separation method which removed poorly fluorescent short tubes and nanotube bundles. Another separation method, ion-exchange chromatography was applied to isolate single chirality SWNTs and perform multicolor NIR imaging in vitro and in vivo. Finally, these bright, biocompatible nanotube fluorophores were used to achieve video rate imaging of mice in vivo during tail vein injection for dynamic contrast enhanced imaging through principal component analysis. The emission in the NIR II region allowed crisp anatomical resolution, confirmed by mock tissue phantom studies and Monte Carlo simulation
DNA-mediated fusion of lipid vesicles by Bettina Van Lengerich( )

1 edition published in 2012 in English and held by 2 WorldCat member libraries worldwide

Vesicle fusion is a central process in transport and communication in biology. In neuronal transmission, synaptic vesicles carrying neurotransmitters dock and fuse to the plasma membrane of the neuron, a process mediated by a combination of several membrane anchored and soluble proteins. Fusion results in the merger of the two apposing lipid bilayers, leading to the exchange of both the lipidic and aqueous components. The fusion reaction is thought to proceed through several stages: first, the membranes are brought into close proximity (docking), second, the outer leaflets mix, but the inner leaflets and contents remain separate (hemi-fusion), and finally, the inner leaflet and contents exchange (full fusion). Due to the complex nature of the fusion reaction and the multitude of proteins involved, the mechanism of the fusion reaction is not well understood. Simplified model systems for vesicle fusion can bring insight into the mechanism by studying the fusion reaction in a more defined and controllable system. This thesis describes a DNA-based model for the protein fusion machinery. Previously, DNA-lipids were used to tether lipid vesicles to glass-supported lipid bilayers. These vesicles could be observed by fluorescence microscopy, and are laterally mobile along the plane parallel to the supported bilayer. DNA-mediated docking between vesicles was characterized, but fusion was not observed due to the fact that the DNA partners were both coupled at the 5' end, so antiparallel hybridization holds the membranes apart. In this work, a new synthesis of DNA-lipid conjugates is described which allows coupling at both the 3' and 5' end of the DNA. Incorporation of complementary DNA-lipids coupled at opposite ends mediates fusion between lipid vesicles. Vesicle fusion was measured in bulk fluorescence assays (Chapter 2 and 3), by both lipid mixing and content mixing assays. The rate of vesicle fusion showed a strong dependence on the number of DNA per vesicle, as well as the sequence of the DNA. Consistent with previous results measured for the docking reaction, fusion was faster for a repeating DNA sequence than for a non-repeating sequence that required full overlap of the strands for hybridization. The role of membrane proximity on the rate of vesicle fusion was investigated in Chapter 3 by insertion of a short spacer sequence at the membrane-proximal end of fusion sequences. The length of the spacer sequence was varied between two and 24 bases, corresponding to length scales of approximately 1-12 nm. Fusion, as measured in bulk assays by lipid and content mixing, decreases systematically as the membranes are held progressively further apart, demonstrating a clear dependence of the rate of the fusion reaction on membrane proximity. While the bulk vesicle fusion assays showed that DNA-lipids can mediate vesicle fusion, these ensemble measurements convolve the multiple steps (docking, hemifusion, and full fusion) of the fusion reaction, complicating any kinetic analysis. In order to image individual vesicle fusion events between tethered vesicles, a new tethering strategy was developed (Chapter 4). This strategy exploits the dependence of DNA hybridization on salt by covalently attaching lipid vesicles to a glass-supported lipid bilayer, then triggering DNA-mediated docking and fusion by spiking the salt concentration. The kinetics of individual vesicle fusion events were subsequently measured using a FRET-based lipid mixing assay for many vesicles (Chapter 6). An analysis of the distribution of waiting times from docking to fusion indicated that this transition occurs in a single step. A second model membrane architecture was used to study individual fusion events between vesicles and a planar bilayer (Chapters 5 and 6). This architecture uses a DNA-tethered planar free-standing bilayer as the target membrane. The kinetics of individual vesicle fusion events to this membrane patch were also consistent with a single step process, as for vesicle to vesicle fusion. In this system, it was also possible to observe content transfer of vesicles containing a self-quenched aqueous dye (Chapter 5). By analyzing the diffusion profile of the dye, it was shown that the dye indeed is transferred into the region below the planar membrane patch, and is not released into the solution above the patch due to vesicle rupture or leakage
Enabling ab initio molecular dynamics for large biological molecules. by Ivan Vasilʹevich Ufimt︠s︡ev( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

The role of atomistic modeling of molecules and organic compounds in biology and pharmaceutical research is constantly increasing, providing insights on chemical and biological phenomena at the highest resolution. To achieve relevant results, however, computational biology has to deal with systems containing at least 1000 atoms. Such big molecules cause large computational demands and impose limitations on the level of theory used to describe molecular interactions. Classical molecular mechanics based on various empirical relationships has become a workhorse of computational biology, as a practical compromise between accuracy and computational cost. Several decades of classical force field development have seen many successes. Nevertheless, more accurate treatment of bio-molecules from first principles is highly desirable. Hartree-Fock (HF) and density functional theory (DFT) are two low-level ab initio methods that provide sufficient accuracy to interpret experimental data. They are therefore the methods of choice to study large biological systems. Recently DFT has been applied to calculate single point energy of a solvated Rubredoxin protein. The system contained 2825 atoms and required more than two hours on a supercomputer with 8196 parallel cores. This study clearly demonstrates the scale of problems one has to tackle in first principles calculations of biologically relevant systems. Dynamical simulations requiring thousands of single point energy and force evaluations therefore appear to be completely out of reach. This fact has essentially prohibited the use of first principles methods for many important biological systems. Fortunately, the computer industry is evolving quickly and novel computing architectures such as graphical processing units (GPUs) are emerging. The GPU is an indispensable part any modern desktop computer. It is special purpose hardware responsible for graphics processing. Most problems in computer graphics are embarrassingly parallel, meaning they can be split into a large number of smaller subproblems that can be solved in parallel. This fact has guided GPU development for more than a decade; and modern GPUs evolved into a massively parallel computing v architecture containing hundreds of basic computational units, which all together can perform trillions of arithmetic operations per second. The large computational performance and low price of consumer graphics cards makes it tempting to consider using them for computationally intensive general purpose computing. This fact was recognized long ago and several groups of enthusiasts attempted to use GPUs for non-graphics computing in the early 2000's. One of the few successes from these attempts is now known as Folding@Home. These early attempts were primarily stymied by three major problems: lack of adequate development frameworks, limited precision available on GPUs, and the difficulty of mapping existing algorithms onto the new architecture. The two former impediments have been recently alleviated by the introduction of efficient GPU programming toolkits such as CUDA and the latest generation of graphics cards supporting full double precision arithmetic operations in hardware. These advances led to an explosion of interest in general purpose GPU computing and led to the development of many GPU-based high performance applications in various fields such as classical molecular dynamics, magnetic resonance imaging, and computational fluid dynamics. Most of the projects, however, lie far outside of quantum chemistry which is likely caused by the complexity of quantum chemistry algorithms and the associated difficulty of mapping them onto the GPU architecture. Various specific features of the hardware require complete redesign of conventional HF and DFT algorithms in order to fully benefit from the large computational performance of GPUs. We have successfully solved this problem and implemented the new algorithms in TeraChem, a high performance general purpose quantum chemistry package designed for graphical processing units from the ground up. Using TeraChem, we performed the first ab initio molecular dynamics simulation of an entire Bovine pancreatic trypsin inhibitor (BPTI) protein for tens of picoseconds on a desktop workstation with eight GPUs operating in parallel. Coincidently, this was also the first protein ever simulated on a computer using the classical molecular mechanics approach. BPTI binds to trypsin with a binding free energy of approximately 20 kcal/mol, making BPTI one of the strongest non-covalent binders. It vi is even more remarkable that a single BPTI amino acid LYS15 contributes half of the binding free energy by forming a salt bridge with one of the trypsin's negatively charged residues inside the binding pocket. In fact, the LYS15's contribution to the overall binding energy is approximately twice as large as what would be expected based on experimental measurements of salt bridge interactions in other proteins. Our simulation of BPTI demonstrated that substantial charge transfer occurs at the proteinwater interface, where between 2.0 and 3.5 electrons are transferred from the interfacial water to the protein. This effect decreases the net protein charge from +6e as observed in gas-phase experiments to +4e or less. We demonstrate how this effect may explain the unusual binding affinity of the LYS15 amino acid
Multifunctional graphitic carbon nanomaterials for imaging, drug delivery and photothermal therapy by Sarah Paige Sherlock( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

In recent years there has been a growing interest in utilizing nanomaterials for drug delivery and biomedical imaging applications. This work focuses on the development of two multifunctional graphitic-carbon based nanomaterials capable of acting as both drug delivery agents and as contrast agents for either magnetic resonance imaging or near-infrared fluorescence imaging. Both of these agents heat under near-infrared light and are capable of loading chemotherapy drugs making them multifunctional in nature. The first material discussed is a FeCo-graphitic carbon nanocrystal loaded with doxorubicin. Addition of near-infrared photothermal therapy significantly increases the cellular toxicity of these nanocrystals in vitro. Treatment of breast cancer tumors in mice using combined nanocrystal drug delivery and photothermal therapy resulted in complete tumor regression in 45% of mice. The imaging capability of these nanocrystals is demonstrated through high-resolution magnetic resonance imaging of microvessels in rabbits. The potential long-term biodistribution and safety of this material is evaluated. The second graphitic-carbon nanomaterial used in this work is single-walled carbon nanotubes. This material is developed as a deep-tissue fluorescent imaging agent due to their inherit photoluminescence beyond 1 micron. This light emission is demonstrated to be particularly useful for in vivo imaging by minimizing light scattering by tissues leading to crisp anatomical resolution
Saxitoxin-derived probes for the study of voltage-gated sodium channels in living cells and animals by William Hazen Parsons( )

1 edition published in 2013 in English and held by 2 WorldCat member libraries worldwide

Voltage-gated sodium channels (NaV) serve an essential role in physiology. Accordingly, their dysfunction is associated with a number of human diseases and disorders, including epilepsy, cardiac arrhythmias, and chronic pain conditions. Designed by Nature as a chemical weapon, the naturally occurring channel blocker (+)-saxitoxin (STX) can be repurposed as a tool for studying these large integral membrane proteins. Access to new toxin derivatives through de novo synthesis offers a unique strategy to probe NaV structure and function, circumventing key limitations associated with existing methods for studying these proteins. The preparation and electrophysiological evaluation of an expanded library of N21-modified STX analogues is described herein. Characterization of the binding properties of these nanomolar NaV inhibitors has contributed to the development of an enhanced model for the structure of the inner pore of the channel. A select set of STX-fluorophore conjugates that bind reversibly to NaV with submicromolar potency serve as fluorescent markers of channels in living cells to study channel motility in the cell membrane. By contrast, maleimide-conjugated STX derivatives can be engineered to act as irreversible inhibitors of ion conductance when applied to wild-type NaV isoforms. The unique binding behavior of these derivatives has been leveraged to develop a new class of NaV probes for use in live cell imaging experiments and protein profiling studies. Maleimide-toxin conjugates with bioorthogonal reactive groups have been synthesized and can be employed for ligation of visualization and isolation tags to covalently modified channels. Appendage of fluorine-18 to a modified STX affords a probe for studying NaV expression in living subjects. An efficient synthetic route yields a derivative that binds with nanomolar affinity to several NaV isoforms. Biodistribution, autoradiography, and PET-MRI imaging studies demonstrate accumulation of the radiotracer at the site of injury in a rat model of neuropathic pain. This uptake correlates with the previously reported upregulation of NaV isoforms at this site, validating the utility of this probe as a NaV imaging agent. Collectively, these STX derivatives, uniquely available through chemical synthesis, represent a novel set of molecular probes for studying NaV function in vitro and in vivo
 
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controlled identityStanford University

Stanford University. Dept. of Chemistry

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English (43)