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- Title
- DISSECTING THE MECHANISTIC ROLES OF REGULATORS IN MEDIATING AMYLOID-BETA AMYLOIDOGENESIS.
- Creator
- Shen, Fengyun, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
-
Alzheimer’s disease (AD) is a common neurodegenerative disorder. The most recognized disease pathology is the Amyloid-β (Aβ) cascade hypothesis which states that the accumulation of Aβ plaques might be the cause of AD. In the AD brain, Aβ plaques stockpile a variety of molecular components including metals, lipids, nucleic acids, carbohydrates, and peptides, indicating Aβ aggregation might be influenced by these modulators. In this dissertation, we investigated the effects of Zn2+ and...
Show moreAlzheimer’s disease (AD) is a common neurodegenerative disorder. The most recognized disease pathology is the Amyloid-β (Aβ) cascade hypothesis which states that the accumulation of Aβ plaques might be the cause of AD. In the AD brain, Aβ plaques stockpile a variety of molecular components including metals, lipids, nucleic acids, carbohydrates, and peptides, indicating Aβ aggregation might be influenced by these modulators. In this dissertation, we investigated the effects of Zn2+ and carnosine, phospholipids, and β-hairpins on Aβ aggregation to dissect their mechanistic roles in the amyloidogenesis of Aβ. We first systematically studied the kinetic impact of Zn2+ on the aggregation of Aβ40 and Aβ40-M. Our results show that the presence of Zn2+ transforms the Aβ40 aggregation kinetics from a single sigmoidal to a biphasic process, while the aggregation of Aβ40-M is significantly suppressed by Zn2+. We also found that a nature dipeptide, carnosine, remarkably decreases the activity of Zn2+ on modulating Aβ aggregation, although it has a weak direct effect on the peptide aggregation kinetics. Second, we investigated the activities of Aβ40 and Aβ42 in inducing membrane damage and the effects of lipid membranes on the aggregation of these peptides using liposome models containing mitochondrial-specific phospholipid–cardiolipin (CL).
Show less - Date Issued
- 2023
- PURL
- http://purl.flvc.org/fau/fd/FA00014314
- Subject Headings
- Alzheimer's disease, Amyloid beta-Peptides, Neurodegenerative Diseases
- Format
- Document (PDF)
- Title
- PRION FRAGMENT 106-128: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION.
- Creator
- Regmi, Deepika, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
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Misfolding and aggregation of Cellular Prion Protein (PrPc) is a major molecular process involved in the pathogenesis of Prion diseases. An N-terminal portion of the Prion protein, PrP106-128, is a 23-residue peptide fragment characterized by an amphipathic structure with two domains: a hydrophilic N-terminal domain and a hydrophobic C-terminal domain. Here, we studied the aggregation properties of the prion fragment peptide PrP106-128. The results show that the peptide aggregates in a...
Show moreMisfolding and aggregation of Cellular Prion Protein (PrPc) is a major molecular process involved in the pathogenesis of Prion diseases. An N-terminal portion of the Prion protein, PrP106-128, is a 23-residue peptide fragment characterized by an amphipathic structure with two domains: a hydrophilic N-terminal domain and a hydrophobic C-terminal domain. Here, we studied the aggregation properties of the prion fragment peptide PrP106-128. The results show that the peptide aggregates in a concentration-dependent manner in an aqueous solution and that the aggregation is sensitive to pH and the preformed amyloid seeds.Furthermore, we show that the zwitterionic POPC liposomes moderately inhibit the aggregation of PrP(106–128), whereas POPC/cholesterol (8:2) vesicles facilitate peptide aggregation likely due to the increase of the lipid packing order and membrane rigidity in the presence of cholesterol. In addition, anionic lipid vesicles of POPG and POPG/cholesterol above a certain concentration accelerate the aggregation of the peptide remarkably. The strong electrostatic interactions between the N-terminal region of the peptide and POPG may constrain the conformational plasticity of the peptide, preventing insertion of the peptide into the inner side of the membrane and thus promoting fibrillation on the membrane surface. The results suggest that the charge properties of the membrane, the composition of the liposomes, and the rigidity of lipid packing are critical in determining peptide adsorption on the membrane surface and the efficiency of the membrane in catalyzing peptide oligomeric nucleation and amyloid formation.
Show less - Date Issued
- 2023
- PURL
- http://purl.flvc.org/fau/fd/FA00014356
- Subject Headings
- Prion Proteins, Prion diseases, Epigallocatechin gallate, Amyloid
- Format
- Document (PDF)
- Title
- Synthesis and Biological Evaluation of β-hairpin Peptides as Covalent Inhibitors of the PD-1/PD-L1 Immune Checkpoint.
- Creator
- Naylon, Sarah, Roche, Stephane, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
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Protein─protein interactions (PPIs) are essential for cell─cell interactions and cellular signal transduction, which play a crucial role in various human diseases. PPIs involved in cancer immunology pathways, known as immune checkpoints, have been intensely studied, leading to a new approach to cancer therapy. The PD1:PDL1 interaction is one of the most essential immune checkpoints. Studies on PD1:PDL1 showed over ten clinical monoclonal antibodies (mAb) used to treat cancer patients....
Show moreProtein─protein interactions (PPIs) are essential for cell─cell interactions and cellular signal transduction, which play a crucial role in various human diseases. PPIs involved in cancer immunology pathways, known as immune checkpoints, have been intensely studied, leading to a new approach to cancer therapy. The PD1:PDL1 interaction is one of the most essential immune checkpoints. Studies on PD1:PDL1 showed over ten clinical monoclonal antibodies (mAb) used to treat cancer patients. Unfortunately, antibodies do not penetrate the tumor microenvironment well, and clearance from the body is slow, leading to unwanted side effects. There is a significant gap in the drug market between the typical Rule of 5 (Ro5) small-molecule drugs (MW<0.5 kDa, SASA ~150 Å) and large antibodies with molecular weights greater than 40 kDa (SASA >2,000 Å). PPIs remain challenging to modulate by small molecules due to their large, shallow, often dynamic, and water-exposed surfaces lacking well-defined binding pockets. Thus, our lab was drawn to work on large β-hairpin peptides (2-3 kDa) that can potentially mimic the CDR-H3 loops of some of the most potent and clinical anti-PD1 antibodies. Exploration of these β-hairpin peptides provided valuable insights into their folding stability, conformational flexibility, passive membrane permeability, and protein-protein interaction (PPI) blocking activities. Additionally, the rational design of TCIs against PD1, specifically targeting a lysine residue, emerged as a strategy to irreversibly obstruct the PD1:PDL1 protein-protein interaction enhancing potency of the non-covalent inhibitors by taking advantage of their specificity. Meticulous structural analysis, peptide synthesis, and biological evaluations are presented contributing comprehensions into covalent inhibitor development of drugs fbRo5.
Show less - Date Issued
- 2023
- PURL
- http://purl.flvc.org/fau/fd/FA00014353
- Subject Headings
- Cancer--Immunological aspects, Protein-protein interactions, Antibodies, Monoclonal
- Format
- Document (PDF)
- Title
- GULF STREAM INTRUSIONS AS CONDUITS FOR LARVAL FISHES ALONG FLORIDA’S EAST COAST.
- Creator
- Woodward, Caroline, Chérubin, Laurent, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
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The mechanisms of larval fish transport have been rigorously studied in the past several decades, building foundational knowledge of key biological and environmental factors with which to inform decisions about species management. This study has been built upon information gained from previous studies to further elucidate the processes involved at the recruitment stage of larval fishes. Vertical swimming behaviors of larval fishes enable deliberate orientation within the water column to allow...
Show moreThe mechanisms of larval fish transport have been rigorously studied in the past several decades, building foundational knowledge of key biological and environmental factors with which to inform decisions about species management. This study has been built upon information gained from previous studies to further elucidate the processes involved at the recruitment stage of larval fishes. Vertical swimming behaviors of larval fishes enable deliberate orientation within the water column to allow organisms of limited mobility greater control over their horizontal movements. Vertical accumulation patterns of larvae are found to be tightly dependent on the strength of stratification within the water column at nursery entrances, such as estuaries. Onshore currents, such as upwelling and surface intrusions, are found to be conduits for entry into these systems. This study observed and analyzed the influence of intrusions by the Gulf Stream into the Fort Pierce Inlet and the vertical accumulation patterns of late-stage larvae associated with those events. This study incorporated a well-established zooplanktonic abundance sampling technique to achieve two primary goals: (1) to analyze the vertical abundances of larval fishes in stratified flow during Gulf Stream intrusions and (2) to assess the correlation between larval influx and intrusion events. The results of this study show a significant and positive correlation between propagule pressure of larval fishes and incidence of Gulf Stream intrusion events. Whereas previous studies have primarily described the spatiotemporal aspects of larval transport in a broader sense, our findings revealed a greater layer of complexity in the mechanisms of transport by incorporating localized hydrographic features. The information gleaned from these results can inform the ecological considerations of future fisheries management and study efforts via additional understanding about the role of physical oceanographic events in a critical life stage.
Show less - Date Issued
- 2023
- PURL
- http://purl.flvc.org/fau/fd/FA00014263
- Subject Headings
- Gulf Stream (Fla.), Larvae--Dispersal, Fishes--Larvae
- Format
- Document (PDF)
- Title
- Studying the Effects of Lipid Membranes and Polysaccharides on the Amyloidogenicity of Fragments of Amyloid Beta.
- Creator
- Petersen, Katherine, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
-
The amyloid beta (Aβ) peptide has been linked to Alzheimer’s Disease (AD) since the early 1990s. Since then, many studies have characterized the peptide and examined its aggregation process. Aβ is a 40 or 42-residue peptide, composed of a charged N-terminal and hydrophobic C-terminal, that aggregates into characteristic β-sheets forming insoluble plaques in the brains of (AD) patients. In recent years an intermediate oligomeric species has been shown to interact with lipid membranes, largely...
Show moreThe amyloid beta (Aβ) peptide has been linked to Alzheimer’s Disease (AD) since the early 1990s. Since then, many studies have characterized the peptide and examined its aggregation process. Aβ is a 40 or 42-residue peptide, composed of a charged N-terminal and hydrophobic C-terminal, that aggregates into characteristic β-sheets forming insoluble plaques in the brains of (AD) patients. In recent years an intermediate oligomeric species has been shown to interact with lipid membranes, largely resulting in the etiology of AD. In this study, two fragments are used, the 23-residue N-terminal fragment, Aβ23 and the 30-residue C-terminal fragment, Aβ11-40, to better understand the role of the N and C-terminus in the aggregation of Aβ peptide. Aβ11-40 has also been found in the brains of AD patients, playing a biological role in the disease. This study used analytical and biophysical techniques to systematically synthesize, purify, characterize, and study these fragments' aggregation in different conditions. We investigated the effects of lipid membranes on the aggregation of Aβ23 and Aβ11-40 and the activities of these peptides in inducing membrane damage. The results show that the aggregation of Aβ23 was increased in the presence of lipid membranes, likely due to favorable electrostatic interactions. However, the aggregation of Aβ11-40 was not influenced by lipid membranes. A dye leakage study was carried out to study the membrane damage occurring as a result of fragments' interaction with lipid membranes. The results showed that neither fragment had a profound effect on membrane destruction, although the charge of the lipid head seemed to play a role. This work's second study focused on the effect of three specific polysaccharides, heparin, chitosan (CHT), and trimethyl chitosan (TMC), on the aggregation of Aβ23 and Aβ11-40. The results showed that for Aβ23, heparin increased aggregation, while both CHT and TMC decreased aggregation. However, for Aβ11-40, both heparin and CHT did not affect aggregation, while TMC decreased aggregation.
Show less - Date Issued
- 2023
- PURL
- http://purl.flvc.org/fau/fd/FA00014294
- Subject Headings
- Amyloid beta-Peptides, Alzheimer's disease
- Format
- Document (PDF)
- Title
- RESVERAMORPHS AS PROTECTIVE AGENTS AGAINST EPILEPSY: OPTIMIZATION OF REDUCTIVE ALDOL BICYCLIZATION AND ANALOG SYNTHESIS WITH FUNCTIONAL GROUP VARIATION TO ASSESS IMPACT ON BIOACTIVITY.
- Creator
- Jutte, Elyse M., Lepore, Salvatore D., Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
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This work encompasses the synthesis, analysis, and optimization of [3.2.1] all-carbon bridged bicyclic compounds, known as resveramorphs (RVM), Studies were conducted using a Caenorhabditis elegans model, where RVMs were tested for antiseizure capabilities. In both applications, RVMs proved potent with activities in the sub-nanomolar level in one case. A structure-activity relationship (SAR) was hypothesized for the identification of the pharmacophore. The six to seven step synthesis route...
Show moreThis work encompasses the synthesis, analysis, and optimization of [3.2.1] all-carbon bridged bicyclic compounds, known as resveramorphs (RVM), Studies were conducted using a Caenorhabditis elegans model, where RVMs were tested for antiseizure capabilities. In both applications, RVMs proved potent with activities in the sub-nanomolar level in one case. A structure-activity relationship (SAR) was hypothesized for the identification of the pharmacophore. The six to seven step synthesis route towards the RVM analogues is discussed in further detail. The bicyclization of the RVMs is achieved through a reductive aldol reaction. The reaction suffers from selectivity issues leading to multiple bicyclic products. By following a one-factor-at-a-time (OFAT) methodology, attempts at optimization for this reaction were made, however, despite important gains, the overall yields of the bicyclic product remain low. Other products from this reaction have been used to understand the reaction mechanism, which will be the basis for future efforts to further optimize this key step.
Show less - Date Issued
- 2023
- PURL
- http://purl.flvc.org/fau/fd/FA00014288
- Subject Headings
- Epilepsy--Animal models, Bridged Bicyclo Compounds, Resveratrol
- Format
- Document (PDF)
- Title
- Crafting Attractive Non-Covalent Interactions for the Study of β-Hairpins with Long Loops.
- Creator
- Richaud, Alexis D., Roche, Stéphane P., Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
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In this study, we developed a new peptide motif called β-strap (strap = strand + cap) used to fold β-hairpins of varying length. β-Straps are mean to be short sequences (4 to 8 a-amino acids) forming β-sheets using a judicious combination of non-covalent interactions (NCI) to overcome the entropic penalty inherent to long loop closure. Among those, we proved that a couple of CH-π / NH-π interactions from a tryptophan zipper motif were critical to create a stable packing of the structure. To...
Show moreIn this study, we developed a new peptide motif called β-strap (strap = strand + cap) used to fold β-hairpins of varying length. β-Straps are mean to be short sequences (4 to 8 a-amino acids) forming β-sheets using a judicious combination of non-covalent interactions (NCI) to overcome the entropic penalty inherent to long loop closure. Among those, we proved that a couple of CH-π / NH-π interactions from a tryptophan zipper motif were critical to create a stable packing of the structure. To optimize these interactions, we incorporated unnatural tryptophan derivatives having functionalized indole side chains. Finally, the innate ability of the β-strap to bring β-stand in close contact was exploited to promote macrocyclization of long coiled peptides (up to 16 residues). Then, we studied a more complex β-hairpin loop mimics found at the apex of monoclonal antibodies (mAb) complementary determining region 3 (CDR-H3). Using a set of bioinformatics tools, a search of PDB crystal structures revealed that a large set of mAb crystals possess a β-bulge, located at the edge of CDR-H3 loops. A cluster analysis revealed it has an impressive adaptability towards different H3-loop sizes and conformations. In order to evaluate its function in antibodies, we synthesized several β-hairpin models bearing a prototypical β-bulge. By combining short β-straps and the β-bulge, we were able to design β-hairpin peptides mimic of mAb with a variety of lengths and rigidity while retaining a high degree of folding. Starting from pembrolizumab, the most outstanding blocker of the PD-1/PD-L1 checkpoint currently available in clinic, we scoped ~30 CDR-H3 mAb mimics (H3 loop). As a result, several novel β-hairpin peptide inhibitors of the PD-1/PD-L1 pathway were identified (IC50 <0.3 μM).
Show less - Date Issued
- 2023
- PURL
- http://purl.flvc.org/fau/fd/FA00014154
- Subject Headings
- Antibodies, Peptides, Biochemistry, β-Hairpins
- Format
- Document (PDF)
- Title
- AMYLOIDOGENICITY OF THE PEPTIDE FRAGMENT IN MICROTUBULE BINDING REPEAT DOMAIN OF TAU.
- Creator
- Islam, Majedul, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
-
Tau, a microtubule-associated protein, is involved in more than 20 different tauopathic disorders characterized by aberrant intracellular aggregation of tau in the brain. However, it is still unclear how this highly soluble tau protein aggregates inside the brain. Thus, understanding the mechanistic details of tau aggregation is critical for unraveling the underlying pathology of tauopathies and developing effective strategies to inhibit tau aggregation. Herein, we investigated the...
Show moreTau, a microtubule-associated protein, is involved in more than 20 different tauopathic disorders characterized by aberrant intracellular aggregation of tau in the brain. However, it is still unclear how this highly soluble tau protein aggregates inside the brain. Thus, understanding the mechanistic details of tau aggregation is critical for unraveling the underlying pathology of tauopathies and developing effective strategies to inhibit tau aggregation. Herein, we investigated the aggregation of a novel 20-residue model peptide, tau₂₉₈₋₃₁₇, derived from the key microtubule-binding domain of the full sequence tau. Our study demonstrates that tau₂₉₈₋₃₁₇ highly mimics full-length tau's physical and aggregation properties. The fibrillation of the peptide is strongly dependent on external factors. The presence of polyanionic heparin (Hep) significantly promotes the aggregation of this peptide to form amyloid fibrils. The Hep-induced aggregation is sensitive to the ionic strength of the solution, suggesting an important role of electrostatic interactions in the mechanism of Hep-mediated aggregation. In addition, two positively charged polysaccharides, chitosan (CHT) and its quaternary derivative N-trimethyl chitosan (TMC), effectively inhibit Hep-induced aggregation of tau₂₉₈₋₃₁₇ in a concentration-dependent manner. Attractive electrostatic interactions between the positively charged moieties in CHT/TMC and the negatively charged residues of Hep play a critical role in inhibiting Hep–peptide interactions and suppressing peptide aggregation.
Show less - Date Issued
- 2023
- PURL
- http://purl.flvc.org/fau/fd/FA00014211
- Subject Headings
- tau Proteins, Tauopathies, Amyloidogenic Proteins
- Format
- Document (PDF)
- Title
- DIASTEREOSELECTIVE ADDITION OF H-PHOSPHINATES TO ALKENYL KETONES UNDER PHASE-TRANSFER CONDITIONS AND SYNTHESIS OF BRIDGED BICYCLIC COMPOUNDS FOR BIOLOGICAL EVALUATION.
- Creator
- Yadavalli, Krishna Prasad, Lepore, Salvatore D., Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
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In the present dissertation, we discuss the development of a stereoselective method for the production of phosphorus compounds that utilizes a phospha-Michael addition reaction. Separately, the design and synthesis of compounds that contain an all-carbon bridged bicyclic scaffold is reported; these compounds were used in initial SAR studies in different in vivo models. In Chapter one is presented a mechanistic framework to develop a highly diastereoselective method catalyzed by phase transfer...
Show moreIn the present dissertation, we discuss the development of a stereoselective method for the production of phosphorus compounds that utilizes a phospha-Michael addition reaction. Separately, the design and synthesis of compounds that contain an all-carbon bridged bicyclic scaffold is reported; these compounds were used in initial SAR studies in different in vivo models. In Chapter one is presented a mechanistic framework to develop a highly diastereoselective method catalyzed by phase transfer chemistry leading to phosphinate compounds. In this method, phosphinate nucleophiles were added to various alkenyl ketones as Michael acceptors using crown ethers as phase transfer agents to obtain highly diastereoselective products with the generation of a carbon-based quaternary centers. A closed transition state mechanism is proposed to describe the diastereoselectivity observed in the reactions that is consistent with product outcome as established by X-ray crystallography. Analysis using the 31P NMR technique is also reported to ascertain the diastereomeric ratios in product formation. Using products obtained with the newly developed method, we disclose for the first time a novel phospha-heterocycle with high control of stereochemistry. Relative stereochemistry of the phosphorus containing heterocycle was reported using 2D NMR analysis. In Chapter two focus is placed on the use of acrylates as Michael acceptors in both the diastereoselective and enantioselective studies of phospha-Michael addition. In the asymmetric method development, screening of various chiral catalysts and development of HPLC method to quantify the enantiopurity of products obtained under reaction conditions are reported. The role of crown ether catalysts towards diastereoselectivity is reported.
Show less - Date Issued
- 2022
- PURL
- http://purl.flvc.org/fau/fd/FA00014015
- Subject Headings
- Bridged bicyclic compounds, Chemistry, Organic, Organic compounds--Synthesis
- Format
- Document (PDF)
- Title
- MULTIVALENT PROTEIN GLYCOSYLATION: A DRIVING FORCE OF CANCER PROGRESSION AND ALZHEIMER’S DISEASE PATHOGENESIS.
- Creator
- Singh, YashoNandini, Cudic, Maré, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
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Glycosylation is a frequent and heterogeneous post-translational protein modification occurring in all domains of life. Aberrant cell-surface glycosylation is shown to mediate several processes involved in tumor cell proliferation, adhesion, and metastasis. Recent findings linked altered protein glycosylation to Alzheimer’s disease (AD) pathogenesis. One key obstacle in studying functional consequences of glycosylation has been the lack of structurally defined glycopeptide or protein model...
Show moreGlycosylation is a frequent and heterogeneous post-translational protein modification occurring in all domains of life. Aberrant cell-surface glycosylation is shown to mediate several processes involved in tumor cell proliferation, adhesion, and metastasis. Recent findings linked altered protein glycosylation to Alzheimer’s disease (AD) pathogenesis. One key obstacle in studying functional consequences of glycosylation has been the lack of structurally defined glycopeptide or protein model compounds for biochemical studies at the molecular level. For tumor progression, studies are crucial towards understanding the glycan-lectin recognition process tied to deciphering the information contained in glycan structures and for AD, foundational studies are necessary for understanding the role of O-glycosylation in protein processing and its fate toward the amyloid pathway. In chapter 1, a highly O-glycosylated transmembrane and cancer-associated mucin protein, MUC1, is used as a model for designing synthetic tools for exploring its role in metastasis via association with lectins and specificity of anti-MUC1 antibodies. This dissertation for the first time presents a MUC1-based positional scanning synthetic glycopeptide combinatorial library that varies in the number and location of tumor-associated Tn antigen. The importance of defined structural complexity for evaluating glycan density and glycosylation patterns for binding to Tn-specific plant lectins and anti-MUC1 (mouse) monoclonal antibodies was revealed using an enzyme-linked lectin assay (ELLA). Chapter 2 addressed the growing significance of peptide lectinomimics for recognizing tumor-specific glycans. Fluorescently labelled alanine scan analogues of odorranalectin (OL), a cyclic peptide that exhibits lectin like properties, were screened for binding BSA-conjugated monosaccharides using ELLA. Results revealed that Lys5, Phe7, Tyr9, Gly12, Leu14, and Thr17 were crucial for binding BSA-L-fucose, BSA-Dgalactose and BSA-N-acetyl-D-galactosamine. The thermodynamics of binding of the selected alanine analogues was evaluated by isothermal titration calorimetry. The thermodynamic profile of interactions with asialofetuin exhibits shift to an entropy-driven mechanism compared to fucoidan, which displayed an enthalpy-entropy compensation, typically associated with the carbohydrate-lectin recognition process. Chapter 3 focused on amyloid-precursor protein (APP) O-glycosylation and its role in AD pathogenesis. We synthesized native and Swedish-mutated (glyco)peptides with O-GalNAc moiety on Thr663 and/or Ser667 or Tyr681 to explore the role of glycosylation on conformation, secretase activity, and aggregation kinetics of Aβ40. Our results show that conformation is strongly dependent on external conditions such as buffer ions and solvent polarity as well as internal modifications of (glyco)peptides such as length, O-glycosylation, and Swedish mutation (Lys670Asn/Met671Leu). Furthermore, the level of β-secretase activity significantly increased for the glycopeptides containing the Swedish mutation compared to their nonglycosylated and native counterparts. Lastly, glycopeptides impacted the kinetics of Aβ40 aggregation by significantly increasing the lag phase and delaying aggregation onset, however, this effect was less pronounced for its Swedish-mutated counterparts.
Show less - Date Issued
- 2022
- PURL
- http://purl.flvc.org/fau/fd/FA00013949
- Subject Headings
- Glycosylation, Alzheimer Disease, Lectins
- Format
- Document (PDF)
- Title
- The synthesis of a new polymeric ligand poly[5-(1,3-bis-(2'-pyridylimino)isoindolyloxy)ethylene] (PBPIIIOE).
- Creator
- Jiang, Yi, Florida Atlantic University, Carraher, Charles E., Baird, Donald M., Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
-
A new polymeric ligand, poly[5-(1,3-bis-(2'-pyridylimino) isoindolyloxy)ethylene], was synthesized. At same time, 1,3-bis-(2 '-pyridylimino)-5-hexadecanyloxyisoindoline was also synthesized. These two products were characterized with fourier transform infrared spectrometry, ultraviolet spectrometry, mass spectral analysis and elemental analysis. Their complexes of Cu+2 were prepared.
- Date Issued
- 2000
- PURL
- http://purl.flvc.org/fcla/dt/12663
- Subject Headings
- Ligands, Organometallic polymers
- Format
- Document (PDF)
- Title
- Bioactive terpene production associated with Caribbean gorgonians from the genera Pseudopterogorgia and Eunicea: Discovery of a sustainable production method.
- Creator
- Newberger, Nealie C., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
-
Research directed toward renewable, non-destructive sources of bioactive marine derived compounds, is becoming more important everyday. Marine soft corals known as sea whips are a prolific source of such biologically active compounds. One particular organism, Eunicea fusca, possesses diterpene arabinose glycosides with potent antiinflammatory activity that rival the industry standard indomethicin. Fuscocide B is known to inhibit phorbol myristate acetate (PMA)-induced ear edema in murine...
Show moreResearch directed toward renewable, non-destructive sources of bioactive marine derived compounds, is becoming more important everyday. Marine soft corals known as sea whips are a prolific source of such biologically active compounds. One particular organism, Eunicea fusca, possesses diterpene arabinose glycosides with potent antiinflammatory activity that rival the industry standard indomethicin. Fuscocide B is known to inhibit phorbol myristate acetate (PMA)-induced ear edema in murine models, is a minor secondary metabolite and it is therefore difficult to acquire in large quantities. Alternatively, fuscol and eunicol, are known to have similar antiinflammatory activity and are major secondary metabolites which are structurally similar to fuscocide B and are also produced by E. fusca. We have found that fuscol and eunicol can be extracted from the holobiont, and Symbiodinium (Symbiodinium sp.) cells isolated from E. fusca. Similarly, diterpene glycosides, known as pseudopterosins, have been isolated from the the holobiont, and purified Symbiodinium of Pseudopterogorgia elisabethae. Pseudopterosins are also known to possess anti-inflammatory and analgesic properties superior to that of existing drugs. Since many chemically unique metabolites demonstrating bioactive properties have been introduced into pre-clinical and clinical trials I-III5 and the supply issue has been duly highlighted, it has become advantageous to determine the source of these compounds in each of the above mentioned species and determine if a renewable, non-destructive source can be maintained. Data has been presented suggesting that the actual source of the pseudopterosins is not the coral, but actually the dinoflagellate symbiont associated with Pseudopterogorgia elisabethae. Therefore, we have examined cryopreservation of the dinoflagellate symbionts, induction of terpene biosynthesis in the dinoflagellate symbionts, as well as various cell culture techniques in order to better understand the ecological role of terpene biosynthesis in the symbionts and the host corals. The data obtained in the following studies reveals a bacterial source for the production of bioactive secondary metabolites from Eunicea fusca and lends support to a possible bacterial producing trend in gorgonians.
Show less - Date Issued
- 2006
- PURL
- http://purl.flvc.org/fcla/dt/12224
- Subject Headings
- Biology, Oceanography, Chemistry, Biochemistry, Chemistry, Organic
- Format
- Document (PDF)
- Title
- Photodegradation of 2-mercaptobenzothiazole disulfide and related benzothiazoles.
- Creator
- Zajickova, Zuzana, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
-
Benzothiazoles are heterocyclic compounds used predominantly as rubber vulcanization accelerators. The overall goal of our research was to investigate the photodegradation behavior of 2-mercaptobenzothiazole disulfide, its degradation product 2-mercaptobenzothiazole, and further degradation product benzothiazole. Modern analytical techniques were utilized to follow photodegradation process at arbitrary intervals. A chromatographic method using reverse phase liquid chromatography was developed...
Show moreBenzothiazoles are heterocyclic compounds used predominantly as rubber vulcanization accelerators. The overall goal of our research was to investigate the photodegradation behavior of 2-mercaptobenzothiazole disulfide, its degradation product 2-mercaptobenzothiazole, and further degradation product benzothiazole. Modern analytical techniques were utilized to follow photodegradation process at arbitrary intervals. A chromatographic method using reverse phase liquid chromatography was developed for the separation of benzothiazoles in the irradiated mixture. Direct photolysis of benzothiazole and 2-mercaptobenzothiazole in methanol at 253.7 and 313 nm in the presence or absence of oxygen was investigated at first. Benzothiazole was found to undergo photodimerization into 2,2'-bibenzothiazole, and in the presence of oxygen to give two additional photoproducts - 2-hydroxybenzothiazole and 2-methylbenzothiazole. The major degradation products of 2-mercaptobenzothiazole are benzothiazole and 2-benzothiazolesulfonic acid, with 2,2'-thiobisbenzothiazole, 2,x'-thiobisbenzothiazole (x = 4, 5, 6, 7), and 2-mercaptobenzothiazole disulfide as the minor degradation products. Direct photolysis of 2-mercaptobenzothiazole disulfide was investigated in four different solvents, at two different wavelengths (253.7 and 313 nm) and concentrations in the presence or absence of oxygen. In all cases 2-mercaptobenzothiazole and 2,x'-thiobisbenzothiazole were detected as the degradation products and in acetonitrile 2-thiocyanatobenzothiazole was also detected. A mechanism is proposed to rationalize the formation of photodegradation products. The effects of solvent, irradiation wavelength, and duration of irradiation time, concentration of the starting material and presence or absence of oxygen are summarized as well. It was observed that photodecomposition at 253.7 nm occurred at a much faster rate than at 313 nm and that less concentrated solutions decomposed faster. At higher concentration of 2-mercaptobenzothiazole its disulfide was detected as one of the degradation products. Methylated products were detected in methanol and acetonitrile and photoreaction took longer in polar protic solvents. Oxygenated products were formed in presence of oxygen and the photoreaction was slower as well in comparison to degassed solutions.
Show less - Date Issued
- 2006
- PURL
- http://purl.flvc.org/fcla/dt/12219
- Subject Headings
- Chemistry, Analytical, Chemistry, Physical
- Format
- Document (PDF)
- Title
- The roles of substrate sequence and thermal stability in the collagenolytic action of matrix metalloproteinases.
- Creator
- Minond, Dmitriy, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
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Matrix metalloproteinases are implicated in diseases accompanied by pathological destruction of tissues. Collagen is an important physiological barrier between tissues and therefore the proteases that can cleave intact collagen are of great interest as possible therapeutic targets. The collagenolytic activity of MMPs varies greatly and within the MMP family distinct preferences for collagen types are seen. Subtle variations in sequence, triple-helix local stability, and Gly register were...
Show moreMatrix metalloproteinases are implicated in diseases accompanied by pathological destruction of tissues. Collagen is an important physiological barrier between tissues and therefore the proteases that can cleave intact collagen are of great interest as possible therapeutic targets. The collagenolytic activity of MMPs varies greatly and within the MMP family distinct preferences for collagen types are seen. Subtle variations in sequence, triple-helix local stability, and Gly register were hypothesized to be among the determinants that may guide these specificities. In order to develop collagenolysis-based inhibitors, we need to examine the interactions between MMPs and collagen on a molecular level. We utilized FRET triple-helical substrates to compare the triple-helical peptidase activities and effects of hypothesized specificity determinants on triple-helical peptidase activities of collagenolytic MMPs. Kinetic parameters of triple-helical peptide hydrolysis were determined for MMP-1, -8, -13, MT1-MMP, and MT2-MMP, and activation energies for this process were calculated. It was determined that MMPs possess differential abilities to process more thermally stable triple-helices. MMP-13 was least sensitive and MMP-1 and MT1-MMP were most sensitive to the enhanced thermal stability of substrates. In agreement with kinetic parameters, hydrolysis of more thermally stable substrates required higher activation energies. MMP collagen specificity also has been examined using a triple-helical substrate library. The consensus type I-III collagen sequence was modified in positions P1' and P2. Single substitution of Gln by Orn in P2 position was beneficial for MMP-13 and MT2 MMP while detrimental for MMP-1, MMP-2, MMP-8, and MT1-MMP activities. Single substitution of Leu by Cys(Mob) in P1' position was disfavored by MMP-1, -2, and -9 and favored by MMP-8, MMP-13, MT1-MMP, and MT2-MMP. Assays of MMP reactions with a sequence containing substitutions in both positions revealed that these sites are not independent from each other, which might indicate an enzyme "induced fit". The significance of triple-helicity for MMP substrate specificity was evaluated by using a library of peptides containing interruptions of Gly register in the vicinity of the scissile bond. Interruption of the Gly register led to the decreased triple-helicity of substrates and subsequently to the inability of membrane type MMPs to cleave such substrates within the interrupted region.
Show less - Date Issued
- 2006
- PURL
- http://purl.flvc.org/fcla/dt/12212
- Subject Headings
- Chemistry, Biochemistry
- Format
- Document (PDF)
- Title
- Conopeptidomics of Conus regius.
- Creator
- Franco, Aldo, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
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The main objective of this dissertation is the isolation and characterization of novel neuroactive peptides from Conus regius. The conopeptides targeted in this work have a MW of 3500 Da or less, in the hopes that they can become viable drug candidates. A total of 30 sequences were isolated and characterized from the venom of Conus regius, giving us a partial library of the conopeptides found in this species. Techniques such as size exclusion chromatography, reversed phase chromatography,...
Show moreThe main objective of this dissertation is the isolation and characterization of novel neuroactive peptides from Conus regius. The conopeptides targeted in this work have a MW of 3500 Da or less, in the hopes that they can become viable drug candidates. A total of 30 sequences were isolated and characterized from the venom of Conus regius, giving us a partial library of the conopeptides found in this species. Techniques such as size exclusion chromatography, reversed phase chromatography, mass spectrometry, nano-nuclear magnetic resonance, chemical modifications of peptides, peptide sequencing through Edman degradation and in some instances bioassays were used together in an effort to perform "conopeptidomics" of Conus regius. The first chapter deals with Conus regius M-superfamily conopeptides. The second chapter is about the A-superfamily conopeptides found in Conus regius. The third chapter deals with Conus regius P-superfamily conopeptides. Finally the fourth chapter encompasses the T-superfamily conopeptides and all other small and linear peptides found in Conus regius that do not have a classification. This work is the first example reported, for any cone snail species, where most of the components of the venom have been sequenced directly for a single cone snail species. This work shows that a more realistic library of conopeptides can be obtained by direct analysis of the venom as opposed to cDNA libraries, which while useful; it does not reflect the post-translational modifications commonly found in conopeptides.
Show less - Date Issued
- 2006
- PURL
- http://purl.flvc.org/fcla/dt/12206
- Subject Headings
- Chemistry, Biochemistry
- Format
- Document (PDF)
- Title
- The d(3,7) non-cubic ligand field spectrum and the electronic spectra of quadrate chromium (III) complexes.
- Creator
- Williams, Chamindra S., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
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In the first-part of this two-part study, the quadrate energy levels of the d3 configuration including spin-orbit interaction are derived in the rare-earth coupling scheme using ligand-field symmetry parameters Dq, Ds, and Dt, by the method of tensor-operators. Comparison is made to the strong field coupling scheme. In the second part of this study, interpretation of polarised single-crystal spectra of trans-[Cr(tmd)2F2]ClO4, trans-[Cr(en)2(dma)2](ClO4) 3, trans-[Cr(en)2(dmf)Br](ClO4) 2 and...
Show moreIn the first-part of this two-part study, the quadrate energy levels of the d3 configuration including spin-orbit interaction are derived in the rare-earth coupling scheme using ligand-field symmetry parameters Dq, Ds, and Dt, by the method of tensor-operators. Comparison is made to the strong field coupling scheme. In the second part of this study, interpretation of polarised single-crystal spectra of trans-[Cr(tmd)2F2]ClO4, trans-[Cr(en)2(dma)2](ClO4) 3, trans-[Cr(en)2(dmf)Br](ClO4) 2 and trans-[Cr(en)2(dmf)Cl](ClO4) 2 as well as unpolarised single-crystal spectrum of trans-[Cr(en) 2(dmf)2](ClO4)3 and solution spectra of trans-[Cr(pn)(en)F2]ClO4, trans-[Cr(en)2FCl]ClO4 and trans-[Cr(en) 2FBr]ClO4 is made using Gaussian analysis of the bands in both polarisations where possible. Ligand field parameters Dq, Ds, Dt and B are extracted from the spectra using energy matrices in the strong-field coupling scheme by fitting the quadrate components of the two lowest energy cubic quartet bands exactly. Discussion of these parameters and the translated AOM (angular overlap model) parameters, is presented. A thorough interpretation of the high-energy intraconfigurational doublet bands in a number of trans-diacidobis (ethylenediamine) chromium (111) complexes is made using quadrate energy matrices including spin-orbit interaction. Entire programming code for the energy matrices in the rare-earth coupling scheme is included, as are procedures for computing 3-j and 6-j symbols. The complete quadrate energy matrices for d3 configuration in the strong-field coupling scheme with spin-orbit perturbation as well quadrate energy matrices for d3 configuration in the rare-earth coupling scheme are included.
Show less - Date Issued
- 2005
- PURL
- http://purl.flvc.org/fcla/dt/12180
- Subject Headings
- Chemistry, Inorganic, Chemistry, Physical
- Format
- Document (PDF)
- Title
- Structural determination of nanomolar quantities of neuroactive peptides by nuclear magnetic resonance.
- Creator
- Matei, Elena, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
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The specificity of the conotoxin is one of the attributes that make them a valuable diagnostic tool in the characterization of neuronal mechanisms, or therapeutic agents in medicine. It appears that Nature has provided us with a pharmaceutical tool in the form of Conus peptides. Further studies will only enhance our understanding, and use, of these molecules in medicine and science. The study of three-dimensional structure in relation to the function of cone snail peptides is an area of...
Show moreThe specificity of the conotoxin is one of the attributes that make them a valuable diagnostic tool in the characterization of neuronal mechanisms, or therapeutic agents in medicine. It appears that Nature has provided us with a pharmaceutical tool in the form of Conus peptides. Further studies will only enhance our understanding, and use, of these molecules in medicine and science. The study of three-dimensional structure in relation to the function of cone snail peptides is an area of increasing interest. The venom of a single cone snail can contain as many as 300 different chemical components. Individual cone snail venom components, or conopeptides, can have powerful neurological effects. For many interesting species, not enough venom collected from the natural origin is available for experimental investigations. After a laborious separation procedure, only nanomole quantities of these native conopeptides are able to be obtained. Therefore, several experimental applications, such as NMR spectroscopy, are difficult to carry out using traditional methods. The research was focused on using nanoNMR spectroscopy as an alternative method to the conventional NMR spectroscopy method in order to analyze small quantities of novel peptides with unknown three-dimensional conformational arrangement. The experimental results obtained using the HR-MAS NMR technique, in addition to the use of a 3mm gHCN (with 1.7mm inserts) NMR probes, proved the capability of conformational analysis of different types of natural products at sample levels down to nanomole range. Understanding the interaction between agonist or antagonist ligands and their target receptors, at a molecular level, offer promise for the development of pharmacological therapeutics for the central nervous system. Conopeptides are of great interest as ligands in neuroscience and are valuable leads in drug design, based on their specificity and potency for therapeutically relevant receptors and ion channels. For instance, the compound called Prialt (formerly known as Ziconotide), a synthetic form of a cone snail-derived peptide, is the most powerful painkiller known and has already received the Food and Drug Administration (FDA) approval. The drug is part of a new class known as the N-type calcium channel blockers, which are responsible for transmitting pain signals. Several related cone snail drugs are currently in clinical trials and could eventually be used to treat different diseases such as Alzheimer's, epilepsy and Parkinson's.
Show less - Date Issued
- 2005
- PURL
- http://purl.flvc.org/fcla/dt/12162
- Subject Headings
- Physics, General, Biophysics, General
- Format
- Document (PDF)
- Title
- Natural products biosynthesis in the gorgonian Eunicea fusca and other marine invertebrates.
- Creator
- Saleh, Maysoon Baker, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
-
Marine organisms represent a rich source of bioactive secondary metabolites. These bioactive compounds are often present in trace quantities in the organism and their clinical development has been hampered by lack of an available supply. The supply problem can be addressed by a chemical synthesis or through biological methods such as aquaculture, cell culture or enzymatic means. The overall goal of this research was to conduct biosynthetic studies of the marine alkaloids ET 743 and stevensine...
Show moreMarine organisms represent a rich source of bioactive secondary metabolites. These bioactive compounds are often present in trace quantities in the organism and their clinical development has been hampered by lack of an available supply. The supply problem can be addressed by a chemical synthesis or through biological methods such as aquaculture, cell culture or enzymatic means. The overall goal of this research was to conduct biosynthetic studies of the marine alkaloids ET 743 and stevensine, and the diterpenes fuscol and fuscoside A-D. The motivation for this is that biosynthetic data could be used to develop a biotechnological production method. ET 743, an anti-cancer agent, is the main alkaloid produced by Ecteinascidia turbinata. Since DKP of DOPA is a key intermediate in ET 743 biosynthesis and since the chemical synthesis of DOPA derivatives is problematic, we developed an enzymatic production method using tyrosine hydroxylase as a tool to oxidize DKP of tyrosine to DKP of DOPA. Stevensine and oroidin are bromopyrrole alkaloids isolated from the marine sponge Axinella corrugate. Stevensine exhibits antimicrobial activity as well as cytotoxicity in vitro against murine leukemia cells. We were able to develop an enzyme based method to identify the amino acids precursors for Stevensine and oroidin using a cell-free extract of the sponge. Fuscosides are diterpene arabinose glycosides isolated from the Caribbean soft coral Eunicea fusca. They and the aglycone fuscol are potent anti-inflammatory compounds with long-lasting effect and have a selective inhibitory action against leukotriene production in murine models of inflammation. We identified and confirmed the intermediary of the diterpenes cyclase product using radioactivity-guided isolation. Furthermore, we completed the elucidation of fuscol biosynthetic pathway. We provided evidence for the use of these diterpenes as oxygen scavengers in the organism. In addition, we investigated the biosynthetic source of the diterpenes in E. fusca and we provided direct evidence for their production by the microbes (bacteria or fungi) present in the organism.
Show less - Date Issued
- 2005
- PURL
- http://purl.flvc.org/fcla/dt/12147
- Subject Headings
- Chemistry, Biochemistry
- Format
- Document (PDF)
- Title
- Studies on the base-promoted conversion of conjugated alkynyl esters to alpha-substituted alpha-allenyl esters.
- Creator
- He, Yuanjun, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
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We report here the development of an efficient method for the conversion of a variety of conjugated alkynyl esters to alpha-substituted conjugated allenyl esters (racemic) through the use of strong amide bases. Substantially improved yields over typical enolate formation conditions were observed with the use of two equivalents of lithium diisopropylamide. Trapping studies indicate that the second equivalent of base likely leads to the dianion intermediate which upon addition of methyl iodide...
Show moreWe report here the development of an efficient method for the conversion of a variety of conjugated alkynyl esters to alpha-substituted conjugated allenyl esters (racemic) through the use of strong amide bases. Substantially improved yields over typical enolate formation conditions were observed with the use of two equivalents of lithium diisopropylamide. Trapping studies indicate that the second equivalent of base likely leads to the dianion intermediate which upon addition of methyl iodide and trimethylsilyl chloride gives mixtures of alpha-substituted conjugated allenyl and beta,gamma-alkynyl deconjugated esters. Further optimization revealed that additive salts such as LiCl lead primarily to the allenyl product while the use of HMPA as a cosolvent gives the beta,gamma-alkynyl deconjugated alkylation product. The role of base, base concentration and electrophile on product yield and selectivity is also discussed. The optimized conditions resulting from our study of this reaction establishes this method as a viable synthetic tool for the production of alpha-substituted allenyl esters. A new method to prepare racemic alpha-tributylstannyl-alpha-allenyl esters from precursor conjugated alkynyl esters in good yields is reported. Key features of the optimized reaction conditions include the use of multiple equiv. of lithium diisopropylamide in THF with LiCl as a key additive. The allenyl tin reagent reacts with aldehydes in the presence of Lewis acid to give homopropargyl alcohol or allenyl alcohol products depending on the reaction conditions. The addition of boron trifluoride etherate to a solution of the allenyltin and aldehyde gives the homopropargyl alcohol. However, allenyl alcohol products are obtained exclusively with the addition of tin tetrachloride to the allenyl stannane rapidly followed by the addition of aldehyde. The effect of other Lewis acids and reaction variables such as solvent and temperature on the yield and relative stereochemistry of the products will also be described. The Mitsunobu coupling reaction of sterically hindered phenols and alcohols is greatly accelerated by the use of high reaction concentration in combination with sonication. The rate acceleration effect observed with our protocol may simply be based on the high concentration with the sonic waves providing efficient mixing of the highly viscous reaction mixture and generating localized hot spots, or in part, the result of an enhancement of a radical reaction pathway.
Show less - Date Issued
- 2005
- PURL
- http://purl.flvc.org/fcla/dt/12120
- Subject Headings
- Chemistry, Organic
- Format
- Document (PDF)
- Title
- Synthesis and structural characterization of intermediates towards the preparation of a polyphosphonate ester containing L-dopa for the potential treatment of Parkinson's disease.
- Creator
- Chamely-Wiik, Donna M., Florida Atlantic University, Haky, Jerome E., Carraher, Charles E., Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
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We have synthesized intermediates towards the preparation of a polyphosphonate ester containing L-dopa for the potential treatment of Parkinson's disease. A synthetic strategy was devised to be more reproducible than the original strategy. We discovered some very interesting chemistry of one of the intermediates produced from this new scheme. We synthesized L-N-(butyloxycarbonyl)-3-(3-hydroxy-ethyl-4-(benzyloxy)-phenyl)alanine benzylester, a compound containing a secondary alcohol moiety that...
Show moreWe have synthesized intermediates towards the preparation of a polyphosphonate ester containing L-dopa for the potential treatment of Parkinson's disease. A synthetic strategy was devised to be more reproducible than the original strategy. We discovered some very interesting chemistry of one of the intermediates produced from this new scheme. We synthesized L-N-(butyloxycarbonyl)-3-(3-hydroxy-ethyl-4-(benzyloxy)-phenyl)alanine benzylester, a compound containing a secondary alcohol moiety that had a unique set of characteristics. Upon reduction of the N-(tert-butyloxycarbonyl)-3-(3-acetyl-4-benzyloxyphenyl)-L-alanine benzylester, which contained a ketone moiety, to produce the secondary alcohol, we discovered that the materials that were formed included a pair of diastereomers of the secondary alcohol, each diastereomer also exhibiting two individually stable conformational isomers. We believe that the conformational isomers were generated by rotation of the C-N bond of the BOC carbamate, and were so stable that they could be separated by HPLC and NMR techniques. Energy optimization studies and molecular modeling techniques were performed using HyperChem, and rotational barrier energy values were calculated for the different conformational isomers for each of the diastereomers. HPLC and NMR techniques were also used to obtain information about these materials. Using the calculated data from these studies, and analyzing the HPLC chromatograms and NMR spectra we were able to fully determine the assignments for the diastereomers and the individual conformational isomers. We discovered that the SS form was synthesized preferentially over the SR form and that in both cases the E conformation was energetically more stable than the Z form. Octanol/water partition coefficient values (Log P0ct) were also determined and compared to L-dopa and dopamine. We concluded that the values for the dimeric compound that we synthesized and many of its potential products of degradation were significantly higher than that for both L-dopa and dopamine. This may be an indication that this material has a higher degree of lipophilicity than L-dopa itself, having more potential to cross the blood brain barrier. We believe that these intermediate materials serve as good indication of how a polyphosphonate ester containing L-dopa would compare as a potential drug for Parkinson's disease.
Show less - Date Issued
- 2004
- PURL
- http://purl.flvc.org/fcla/dt/12108
- Subject Headings
- Parkinson's disease--Treatment, Antiparkinsonian agents, Dopa, Organophosphorus compounds--Synthesis, Chemistry, Analytic
- Format
- Document (PDF)