Matching Items (7)
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Description
ABSTRACT

Transition metals have been extensively employed to address various challenges

related to catalytic organic transformations, small molecule activation, and energy storage

over the last few decades. Inspired by recent catalytic advances mediated by redox noninnocent

pyridine diimine (PDI) and α-diimine (DI) ligand supported transition metals,

our group has designed new PDI and DI ligands

ABSTRACT

Transition metals have been extensively employed to address various challenges

related to catalytic organic transformations, small molecule activation, and energy storage

over the last few decades. Inspired by recent catalytic advances mediated by redox noninnocent

pyridine diimine (PDI) and α-diimine (DI) ligand supported transition metals,

our group has designed new PDI and DI ligands by modifying the imine substituents to

feature donor atoms. My doctoral research is focused on the development of PDI and DI

ligand supported low valent first row metal complexes (Mn, Fe, Co) and their application

in bond activation reactions and the hydrofunctionalization of unsaturated bonds.

First two chapters of this dissertation are centered on the synthesis and

application of redox non-innocent ligand supported low valent iron complexes. Notably,

reduction of a DI-based iron dibromide led to the formation of a low valent iron

dinitrogen compound. This compound was found to undergo a sequential C-H and C-P

bond activation processes upon heating to form a dimeric compound. The plausible

mechanism for dimer formation is also described here.

Inspired by the excellent carbonyl hydrosilylation activity of our previously

reported Mn catalyst, (Ph2PPrPDI)Mn, attempts were made to synthesize second generation

Mn catalyst, which is described in the third chapter. Reduction of (PyEtPDI)MnCl2

furnished a deprotonated backbone methyl group containing Mn compound

[(PyEtPDEA)Mn] whereas reduction of (Ph2PEtPDI)MnCl2 produced a dimeric compound,

[(Ph2PEtPDI)Mn]2. Both compounds were characterized by NMR spectroscopy and XRD

analysis. Hydrosilylation of aldehydes and ketones have been studied using

[(PyEtPDEA)Mn] as a pre-catalyst. Similarly, 14 different aldehydes and 6 different

ii

formates were successfully hydrosilylated using [(Ph2PEtPDI)Mn]2 as a pre-catalyst.

Encouraged by the limited number of cobalt catalysts for nitrile hydroboration, we

sought to develop a cobalt catalyst that is active for hydroboration under mild conditions,

which is discussed in the last chapter. Treatment of (PyEtPDI)CoCl2 with excess NaEt3BH

furnished a diamagnetic Co(I) complex [(PyEtPDIH)Co], which exhibits a reduced imine

functionality. Having this compound characterized, a broad substrate scope for both

nitriles and imines have been investigated. The operative mechanism for nitrile

dihydroboration has been investigated based on the outcomes of a series of stoichiometric

reactions using NMR spectroscopy.
ContributorsGhosh, Chandrani (Author) / Trovitch, Ryan J. (Thesis advisor) / Seo, Don (Committee member) / Moore, Ana (Committee member) / Arizona State University (Publisher)
Created2018
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Description
Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor

Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor and in return control cell differentiation and proliferation. Bexarotene targets RXR homodimerization to drive transcription of tumor suppressing genes; however, adverse reactions occur simultaneously when bound to other nuclear receptors. In this study, we used novel bexarotene analogs throughout 5 iterations synthesized in the laboratory of Dr. Wagner to test for their potency and ability to bind RXR. The aim of our study is to quantitatively measure RXR homodimerization driven by bexarotene analogs using a yeast two-hybrid system. Our results suggests there to be several compounds with higher protein activity than bexarotene, particularly in generations 3.0 and 5.0. This higher affinity for RXR homodimers may help scientists identify a compound that will minimize adverse effects and toxicity of bexarotene and serve as a better cancer treatment alternative.
ContributorsSeto, David Hua (Author) / Marshall, Pamela (Thesis director) / Wagner, Carl (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor) / School of Social and Behavioral Sciences (Contributor)
Created2015-05
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Description
Peptides offer great promise as targeted affinity ligands, but the space of possible peptide sequences is vast, making experimental identification of lead candidates expensive, difficult, and uncertain. Computational modeling can narrow the search by estimating the affinity and specificity of a given peptide in relation to a predetermined protein

Peptides offer great promise as targeted affinity ligands, but the space of possible peptide sequences is vast, making experimental identification of lead candidates expensive, difficult, and uncertain. Computational modeling can narrow the search by estimating the affinity and specificity of a given peptide in relation to a predetermined protein target. The predictive performance of computational models of interactions of intermediate-length peptides with proteins can be improved by taking into account the stochastic nature of the encounter and binding dynamics. A theoretical case is made for the hypothesis that, because of the flexibility of the peptide and the structural complexity of the target protein, interactions are best characterized by an ensemble of possible bound configurations rather than a single “lock and key” fit. A model incorporating these factors is proposed and evaluated. A comprehensive dataset of 3,924 peptide-protein interface structures was extracted from the Protein Data Bank (PDB) and descriptors were computed characterizing the geometry and energetics of each interface. The characteristics of these interfaces are shown to be generally consistent with the proposed model, and heuristics for design and selection of peptide ligands are derived. The curated and energy-minimized interface structure dataset and a relational database containing the detailed results of analysis and energy modeling are made publicly available via a web repository. A novel analytical technique based on the proposed theoretical model, Virtual Scanning Probe Mapping (VSPM), is implemented in software to analyze the interaction between a target protein of known structure and a peptide of specified sequence, producing a spatial map indicating the most likely peptide binding regions on the protein target. The resulting predictions are shown to be superior to those of two other published methods, and support the validity of the stochastic binding model.
ContributorsEmery, Jack Scott (Author) / Pizziconi, Vincent B (Thesis advisor) / Woodbury, Neal W (Thesis advisor) / Guilbeau, Eric J (Committee member) / Stafford, Phillip (Committee member) / Taylor, Thomas (Committee member) / Towe, Bruce C (Committee member) / Arizona State University (Publisher)
Created2010
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Description

Rosalyn Sussman Yalow co-developed the radioimmunoassay (RIA), a method used to measure minute biological compounds that cause immune systems to produce antibodies. Yalow and research partner Solomon A. Berson developed the RIA in the early 1950s at the Bronx Veterans Administration (VA) Hospital, in New York City, New York. Yalow

Rosalyn Sussman Yalow co-developed the radioimmunoassay (RIA), a method used to measure minute biological compounds that cause immune systems to produce antibodies. Yalow and research partner Solomon A. Berson developed the RIA in the early 1950s at the Bronx Veterans Administration (VA) Hospital, in New York City, New York. Yalow and Berson's methods expanded scientific research, particularly in the medical field, and contributed to medical diagnostics. For this achievement, Yalow received the Nobel Prize in Physiology or Medicine in 1977. The RIA technique is used to measure more than one hundred biochemical substances, including infectious agents, narcotics, and hormones, such as those used to diagnose infertility and hypothyroidism.

Created2013-09-10
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Description

Solomon A. Berson helped develop the radioimmunoassay (RIA) technique in the US during the twentieth century. Berson made many scientific contributions while working with research partner Rosalyn Yalow at the Bronx Veterans Administration (VA) hospital, in New York City, New York. In the more than twenty years that Berson and

Solomon A. Berson helped develop the radioimmunoassay (RIA) technique in the US during the twentieth century. Berson made many scientific contributions while working with research partner Rosalyn Yalow at the Bronx Veterans Administration (VA) hospital, in New York City, New York. In the more than twenty years that Berson and Yalow collaborated, they refined the procedures for tracing diagnostic biological compounds using isotope labels. In the late 1950s they developed the RIA based on the ability to trace the competition between and ligands, or small molecules that bind to specific sites of other biomolecules, and proteins for the same molecular binding site, a process called competitive binding. Scientists widely used Berson and Yalow's RIA, as these methods permit the use of a minimal sample of blood for accurate measurements of biological molecules such as hormones that cause the production of antibodies. Berson and Yalow's research has advanced the study of physiology, including that of the reproductive system, with particular applications to the diagnosis and treatment of infertility.

Created2013-11-01
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Description
The addition of aminoalkyl-substituted 2,6-bis(imino)pyridine (or pyridine diimine, PDI) ligands to [(COD)RhCl]2 (COD = 1,5-cyclooctadiene) resulted in the formation of rhodium monochloride complexes with the general formula (NPDI)RhCl (NPDI = iPr2NEtPDI or Me2NPrPDI). The investigation of (iPr2NEtPDI)RhCl and (Me2NPrPDI)RhCl by single crystal X-ray diffraction verified the absence of amine arm

The addition of aminoalkyl-substituted 2,6-bis(imino)pyridine (or pyridine diimine, PDI) ligands to [(COD)RhCl]2 (COD = 1,5-cyclooctadiene) resulted in the formation of rhodium monochloride complexes with the general formula (NPDI)RhCl (NPDI = iPr2NEtPDI or Me2NPrPDI). The investigation of (iPr2NEtPDI)RhCl and (Me2NPrPDI)RhCl by single crystal X-ray diffraction verified the absence of amine arm coordination and a pseudo square planar geometry about rhodium. Replacement of the chloride ligand with an outer-sphere anion was achieved by adding AgBF4 directly to (iPr2NEtPDI)RhCl to form [(iPr2NEtPDI)Rh][BF4]. Alternatively, this complex was prepared upon chelate addition following the salt metathesis reaction between AgBF4 and [(COD)RhCl]2. Using the latter method, both [(NPDI)Rh][BF4] complexes were isolated and found to exhibit κ4-N,N,N,N-PDI coordination regardless of arm length or steric bulk. In contrast, the metallation of PPDI chelates featuring alkylphosphine imine substituents (PPDI = Ph2PEtPDI or Ph2PPrPDI) resulted in the formation of cationic complexes featuring κ5-N,N,N,P,P-PDI coordination in all instances, [(PPDI)Rh][X] (X = Cl, BF4). Adjusting the metallation stoichiometry allowed the preparation of [(Ph2PPrPDI)Rh][(COD)RhCl2], which was characterized by multinuclear NMR spectroscopy and single crystal X-ray diffraction.
ContributorsLevin, Hagit Ben-Daat (Author) / Trovitch, Ryan J (Thesis advisor) / Gould, Ian R (Committee member) / Ghirlanda, Giovanna (Committee member) / Arizona State University (Publisher)
Created2016
Description
Due to analytical limitations, thermodynamic modeling is a lucrative alternative for obtaining metal speciation in chemically complex systems like life. However, such modeling is limited by the lack of equilibrium constant data for metal-complexation reactions, particularly for metal-organic species. These problems were ameliorated estimating these properties from 0-125°C for ~18,000

Due to analytical limitations, thermodynamic modeling is a lucrative alternative for obtaining metal speciation in chemically complex systems like life. However, such modeling is limited by the lack of equilibrium constant data for metal-complexation reactions, particularly for metal-organic species. These problems were ameliorated estimating these properties from 0-125°C for ~18,000 metal complexes of small molecules, proteins and peptides.

The estimates of metal-ligand equilibrium constants at 25°C and 1 bar were made using multiple linear free energy relationships in accordance with the metal-coordinating properties of ligands such as denticity, identity of electron donor group, inductive effects and steric hindrance. Analogous relationships were made to estimated metal-ligand complexation entropy that facilitated calculation of equilibrium constants up to 125°C using the van’t Hoff equation. These estimates were made for over 250 ligands that include carboxylic acids, phenols, inorganic acids, amino acids, peptides and proteins.

The stability constants mentioned above were used to obtain metal speciation in several microbial growth media including past bioavailability studies and compositions listed on the DSMZ website. Speciation calculations were also carried out for several metals in blood plasma and cerebrospinal fluid that include metals present at over micromolar abundance (sodium, potassium, calcium, magnesium, iron, copper and zinc) and metals of therapeutic or toxic potential (like gallium, rhodium and bismuth). Metal speciation was found to be considerably dependent on pH and chelator concentration that can help in the selection of appropriate ligands for gallium & rhodium based anticancer drugs and zinc-based antidiabetics. It was found that methanobactin can considerably alter copper speciation and is therefore a suitable agent for the treatment of Wilson Disease. Additionally, bismuth neurotoxicity was attributed to the low transferrin concentration in cerebrospinal fluid and the predominance of aqueous bismuth trihydroxide. These results demonstrate that metal speciation calculations using thermodynamic modeling can be extremely useful for understanding metal bioavailability in microbes and human bodily fluids.
ContributorsPrasad, Apar (Author) / Shock, Everett (Thesis advisor) / Trovitch, Ryan (Committee member) / Redding, Kevin (Committee member) / Arizona State University (Publisher)
Created2019