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You searched for +publisher:"Georgia Tech" +contributor:("Powers, James C."). Showing records 1 – 3 of 3 total matches.

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1. Lucrezi, Jacob. The evaluation of novel anti-inflammatory compounds in cell culture and experimental arthritis and identification of an inhibitor to early-stage loblolly pine somatic embryo growth.

Degree: PhD, Chemistry and Biochemistry, 2013, Georgia Tech

The interactions between the immune and nervous systems play an important role in immune and inflammatory conditions. Substance P (SP), the unidecapeptide RPKPQQFFGLM-NH2, is known to upregulate the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α. We report here that 5 (Acetylamino) 4 oxo-6-phenyl-2-hexenoic acid methyl ester (AOPHA-Me) and 4 phenyl 3 butenoic acid (PBA), two anti-inflammatory compounds developed in our laboratory, reduce SP stimulated TNF-α expression in RAW 264.7 macrophages. We also show that AOPHA Me and PBA both inhibit SP stimulated phosphorylation of JNK and p38 MAPK. Furthermore, molecular modeling studies indicate that both AOPHA Me and PBA dock at the ATP binding site of apoptosis signal regulating kinase 1 (ASK1) with predicted docking energies of -7.0 kcal/mol and 5.9 kcal/mol, respectively; this binding overlaps with that of staurosporine, a known inhibitor of ASK1. Taken together, these findings support the conclusion that AOPHA Me and PBA inhibition of TNF-α expression in SP-stimulated RAW 264.7 macrophages is a consequence of the inhibition JNK and p38 MAPK phosphorylation. We have previously shown that AOPHA-Me and PBA inhibit the amidative bioactivation of SP, which also would be expected to decrease formation of pro-inflammatory cytokines. It is conceivable that this dual action of inhibiting amidation and MAPK phosphorylation may be of some advantage in enhancing the anti-inflammatory activity of a therapeutic molecule. We also encapsulated AOPHA-Me separately in polyketal and poly(lactic co glycolic acid) microparticles. The in-vitro release profiles of AOPHA-Me from these particles were characterized. We have also shown that AOPHA-Me, when encapsulated in PCADK microparticles, is an effective treatment for edema induced by adjuvant arthritis in rats. In separate work, it was determined that myo inositol 1,2,3,4,5,6 hexakisphosphate is an inhibitor to early-stage Loblolly pine somatic embryo growth. In addition, it was determined that muco inositol 1,2,3,4,5,6 hexakisphosphate is not an inhibitor to early-stage Loblolly pine somatic embryo growth. These experiments demonstrate the stereochemical dependence of myo inositol 1,2,3,4,5,6 hexakisphosphates inhibitory activity. Advisors/Committee Members: May, Sheldon W. (advisor), Doyle, Donald (committee member), Hud, Nicholas V. (committee member), Powers, James C. (committee member), Pollock, Stanley H. (committee member).

Subjects/Keywords: Substance P; TNF-alpha; p38 MAPK; JNK; RAW 264.7 macrophages; Loblolly pine; Somatic embryogenesis; Nanoparticle

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APA (6th Edition):

Lucrezi, J. (2013). The evaluation of novel anti-inflammatory compounds in cell culture and experimental arthritis and identification of an inhibitor to early-stage loblolly pine somatic embryo growth. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/52969

Chicago Manual of Style (16th Edition):

Lucrezi, Jacob. “The evaluation of novel anti-inflammatory compounds in cell culture and experimental arthritis and identification of an inhibitor to early-stage loblolly pine somatic embryo growth.” 2013. Doctoral Dissertation, Georgia Tech. Accessed March 06, 2021. http://hdl.handle.net/1853/52969.

MLA Handbook (7th Edition):

Lucrezi, Jacob. “The evaluation of novel anti-inflammatory compounds in cell culture and experimental arthritis and identification of an inhibitor to early-stage loblolly pine somatic embryo growth.” 2013. Web. 06 Mar 2021.

Vancouver:

Lucrezi J. The evaluation of novel anti-inflammatory compounds in cell culture and experimental arthritis and identification of an inhibitor to early-stage loblolly pine somatic embryo growth. [Internet] [Doctoral dissertation]. Georgia Tech; 2013. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1853/52969.

Council of Science Editors:

Lucrezi J. The evaluation of novel anti-inflammatory compounds in cell culture and experimental arthritis and identification of an inhibitor to early-stage loblolly pine somatic embryo growth. [Doctoral Dissertation]. Georgia Tech; 2013. Available from: http://hdl.handle.net/1853/52969

2. Ovat, Asli. Design, synthesis and evaluation of cysteine protease inhibitors.

Degree: PhD, Chemistry and Biochemistry, 2009, Georgia Tech

Cysteine proteases are important drug targets due to their involvement in many biological processes such as protein turnover, digestion, blood coagulation, apoptosis, cell differentiation, cell signaling, and the immune response. In this thesis, we have reported the design, synthesis and evaluation of clan CA and clan CD cysteine protease inhibitors. Aza-peptidyl Michael acceptor and epoxide inhibitors for asparaginyl endopeptidases (legumains) from the bloodfluke, Schistosoma mansoni (SmAE) and the hard tick, Ixodes ricinus (IrAE) were designed and synthesized. SARs were similar, but with some notable exceptions. Both enzymes prefer disubstituted amides to monosubstituted amides in the P1' position and potency increased as we increased the hydrophobicity of the inhibitor in this position. Extending the inhibitor to P5 resulted in increased inhibitory potency, especially against IrAE, and both enzymes prefer small over large hydrophobic residues in the P2 position. Aza-peptide Michael acceptor inhibitors are more potent than aza-peptide epoxide inhibitors and, for some of these compounds, second order inhibition rate constants are the fastest yet discovered. We have also synthesized aza-peptidyl Michael acceptor and epoxide inhibitors for the parasitic cysteine proteases; cruzain, rhodesain. We have found that monosubstituted amides were favored over disubstituted amides indicating the involvement of the amide hydrogen in a H-bond network. We have shown that aza-peptide epoxides were as potent as Michael acceptors and we have obtained compounds with IC50 values as low as 20 nM. We have worked on the synthesis of heterocyclic peptidyl α-ketoamides, peptidyl ketones and aza-peptidyl ketones as calpain inhibitors. We have synthesized peptidyl α-ketoamides with nucleotide bases in the primed region to create compounds that can cross the blood-brain barrier. We have improved the potency by introducing a hydrophobic group on the adenine ring. We have obtained compounds with Ki values in the nanomolar range. We have designed peptidyl aminoketones as a new class of inhibitors for calpain. Peptidyl aminoketones were less potent than peptidyl α-ketoamides but still reasonable inhibitors of calpain that have the potential to cross the BBB. Advisors/Committee Members: Powers, James C. (Committee Chair), Christoph J. Fahrni (Committee Member), Jonathan D. Glass (Committee Member), Nicholas V. Hud (Committee Member), Sheldon W. May (Committee Member).

Subjects/Keywords: Legumain; Calpain; Protease; Cysteine; Cysteine proteinases; Cysteine proteinases Inhibitors; Protease inhibitors; Biosynthesis; Epoxy compounds

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APA (6th Edition):

Ovat, A. (2009). Design, synthesis and evaluation of cysteine protease inhibitors. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/33822

Chicago Manual of Style (16th Edition):

Ovat, Asli. “Design, synthesis and evaluation of cysteine protease inhibitors.” 2009. Doctoral Dissertation, Georgia Tech. Accessed March 06, 2021. http://hdl.handle.net/1853/33822.

MLA Handbook (7th Edition):

Ovat, Asli. “Design, synthesis and evaluation of cysteine protease inhibitors.” 2009. Web. 06 Mar 2021.

Vancouver:

Ovat A. Design, synthesis and evaluation of cysteine protease inhibitors. [Internet] [Doctoral dissertation]. Georgia Tech; 2009. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1853/33822.

Council of Science Editors:

Ovat A. Design, synthesis and evaluation of cysteine protease inhibitors. [Doctoral Dissertation]. Georgia Tech; 2009. Available from: http://hdl.handle.net/1853/33822


Georgia Tech

3. Bean, Heather D. Prebiotic synthesis of nucleic acids.

Degree: PhD, Chemistry and Biochemistry, 2008, Georgia Tech

The origin of the first RNA polymers is central to most current theories regarding the origin of life. However, difficulties associated with the prebiotic formation of RNA have lead many researchers to conclude that simpler polymers, or proto-RNAs, preceded RNA. These earlier polymers would have been replaced by RNA over the course of evolution. A remaining difficulty for this theory is that the de novo synthesis of a feasible proto-RNA has not yet been demonstrated by plausible prebiotic reactions. This thesis focuses on two problems associated with prebiotic proto-RNA synthesis: The formation of nucleosides and the necessity of reversible backbone linkages for error correction in nucleic acid polymers. "The Nucleoside Problem", or the lack of success in forming pyrimidine nucleosides by plausible prebiotic reactions, represents a significant stumbling block to the RNA world hypothesis. Nearly four decades ago Orgel and coworkers demonstrated that the purine nucleosides adenosine and inosine are synthesized by heating and drying their respective bases and ribose in the presence of magnesium, but these reaction conditions do not yield the pyrimidine nucleosides uridine or cytidine from their respective bases. In this thesis a potential solution to The Nucleoside Problem is hypothesized based upon a proposed chemical mechanism for nucleoside formation. This hypothesis is supported by the successful synthesis of 2-pyrimidinone nucleosides by a plausible prebiotic reaction in good yield, demonstrating that pyrimidine nucleosides could have been available in the prebiotic chemical inventory, but that uridine and cytidine were likely not abundant. Reversible backbone linkages are necessary to provide a mechanism for error correction in non-enzymatic template-directed syntheses of proto-RNAs. In this thesis, acetals are explored as low-energy, reversible linkage groups for nucleosides in polymers. The synthesis of glyoxylate-acetal nucleic acids (gaNAs) through simple heating-drying reactions from neutral aqueous solutions is demonstrated, and these linkages are shown to be hydrolytically stable under a considerable range of solution conditions. Computational models demonstrate that the glyoxylate linkage is an excellent electronic and isosteric replacement for phosphate. Molecular dynamics simulations also indicate that a gaNA duplex would have structural properties that closely match a phosphate-linked RNA helix, suggesting the possibility for cross-pairing between gaNAs and RNAs, allowing for sequence transfer and genetic continuity through the evolution from proto-RNAs to RNA. The principles illustrated in this thesis by 2-pyrimidinone nucleoside and gaNA synthesis can be extended to other prebiotic condensation reactions. Factors affecting condensation yield, such as thermodynamics, kinetics, reactant solubility, and salt effects, are summarized herein. Advisors/Committee Members: Hud, Nicholas V. (Committee Chair), Fox, Ronald F. (Committee Member), Lynn, David G. (Committee Member), Powers, James C. (Committee Member), Wartell, Roger M. (Committee Member), Williams, Loren D. (Committee Member).

Subjects/Keywords: Glyoxylate; Zebularine; Prebiotic chemistry; Glycosidic bond; Pyrimidine; RNA World; Origin of life; Condensation; Acetal; Nucleic acids Synthesis; Molecular evolution; RNA Evolution; Evolutionary genetics; Life Origin; Pyrimidine nucleotides; Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Bean, H. D. (2008). Prebiotic synthesis of nucleic acids. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/28259

Chicago Manual of Style (16th Edition):

Bean, Heather D. “Prebiotic synthesis of nucleic acids.” 2008. Doctoral Dissertation, Georgia Tech. Accessed March 06, 2021. http://hdl.handle.net/1853/28259.

MLA Handbook (7th Edition):

Bean, Heather D. “Prebiotic synthesis of nucleic acids.” 2008. Web. 06 Mar 2021.

Vancouver:

Bean HD. Prebiotic synthesis of nucleic acids. [Internet] [Doctoral dissertation]. Georgia Tech; 2008. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1853/28259.

Council of Science Editors:

Bean HD. Prebiotic synthesis of nucleic acids. [Doctoral Dissertation]. Georgia Tech; 2008. Available from: http://hdl.handle.net/1853/28259

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