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Description
Mitochondria are crucial intracellular organelles which play a pivotal role in providing energy to living organisms in the form of adenosine triphosphate (ATP). The mitochondrial electron transport chain (ETC) coupled with oxidative phosphorylation (OX-PHOS) transforms the chemical energy of amino acids, fatty acids and sugars to ATP. The mitochondrial electron transport system consumes nearly 90% of the oxygen used by the cell. Reactive oxygen species (ROS) in the form of superoxide anions (O2*-) are generated as byproduct of cellular metabolism due to leakage of electrons from complex I and complex III to oxygen. Under normal conditions, the effects of ROS are offset by a variety of antioxidants (enzymatic and non-enzymatic).
Mitochondrial dysfunction has been proposed in the etiology of various pathologies, including cardiovascular and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, ischemia-reperfusion (IR) injury, diabetes and aging. To treat these disorders, it is imperative to target mitochondria, especially the electron transport chain. One of the methodologies currently used for the treatment of mitochondrial and neurodegenerative diseases where endogenous antioxidant defenses are inadequate for protecting against ROS involves the administration of exogenous antioxidants.
As part of our pursuit of effective neuroprotective drugs, a series of pyridinol and pyrimidinol analogues have been rationally designed and synthesized. All the analogues were evaluated for their ability to quench lipid peroxidation and reactive oxygen species (ROS), and preserve mitochondrial membrane potential (Δm) and support ATP synthesis. These studies are summarized in Chapter 2.
Drug discovery and lead identification can be reinforced by assessing the metabolic fate of orally administered drugs using simple microsomal incubation experiments. Accordingly, in vitro microsomal studies were designed and carried out using bovine liver microsomes to screen available pyridinol and pyrimidinol analogues for their metabolic lability. The data obtained was utilized for an initial assessment of potential bioavailability of the compounds screened and is summarized fully in Chapter 3.
Mitochondrial dysfunction has been proposed in the etiology of various pathologies, including cardiovascular and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, ischemia-reperfusion (IR) injury, diabetes and aging. To treat these disorders, it is imperative to target mitochondria, especially the electron transport chain. One of the methodologies currently used for the treatment of mitochondrial and neurodegenerative diseases where endogenous antioxidant defenses are inadequate for protecting against ROS involves the administration of exogenous antioxidants.
As part of our pursuit of effective neuroprotective drugs, a series of pyridinol and pyrimidinol analogues have been rationally designed and synthesized. All the analogues were evaluated for their ability to quench lipid peroxidation and reactive oxygen species (ROS), and preserve mitochondrial membrane potential (Δm) and support ATP synthesis. These studies are summarized in Chapter 2.
Drug discovery and lead identification can be reinforced by assessing the metabolic fate of orally administered drugs using simple microsomal incubation experiments. Accordingly, in vitro microsomal studies were designed and carried out using bovine liver microsomes to screen available pyridinol and pyrimidinol analogues for their metabolic lability. The data obtained was utilized for an initial assessment of potential bioavailability of the compounds screened and is summarized fully in Chapter 3.
ContributorsAlam, Mohammad Parvez (Author) / Hecht, Sidney M. (Thesis advisor) / Gould, Ian R (Committee member) / Moore, Ana (Committee member) / Arizona State University (Publisher)
Created2014
Description
Cellular redox phenomena are essential for the life of organisms. Described here is a summary of the synthesis of a number of redox-cycling therapeutic agents. The work centers on the synthesis of antitumor antibiotic bleomycin congeners. In addition, the synthesis of pyridinol analogues of alpha-tocopherol is also described. The bleomycins (BLMs) are a group of glycopeptide antibiotics that have been used clinically to treat several types of cancers. The antitumor activity of BLM is thought to be related to its degradation of DNA, and possibly RNA. Previous studies have indicated that the methylvalerate subunit of bleomycin plays an important role in facilitating DNA cleavage by bleomycin and deglycobleomycin. A series of methylvalerate analogues have been synthesized and incorporated into deglycobleomycin congeners by the use of solid-phase synthesis. All of the deglycobleomycin analogues were found to effect the relaxation of plasmid DNA. Those analogues having aromatic C4-substituents exhibited cleavage efficiency comparable to that of deglycoBLM A5. Some, but not all, of the deglycoBLM analogues were also capable of mediating sequence-selective DNA cleavage. The second project focused on the synthesis of bicyclic pyridinol analogues of alpha-tocopherol. Bicyclic pyridinol antioxidants have recently been reported to suppress the autoxidation of methyl linoleate more effectively than alpha-tocopherol. However, the complexity of the synthetic routes has hampered their further development as therapeutic agents. Described herein is a concise synthesis of two bicyclic pridinol antioxidants and a facile approach to their derivatives with simple alkyl chains attached to the antioxidant core. These analogues were shown to retain biological activity and exhibit tocopherol-like behaviour.
ContributorsCai, Xiaoqing (Author) / Hecht, Sidney M. (Thesis advisor) / Gould, Ian R (Committee member) / Hartnett, Hilairy E (Committee member) / Arizona State University (Publisher)
Created2011
Description
The antioxidant, antihistamine, and chemotactic properties of vitamin C provide the theoretical basis linking vitamin C supplementation to combating the common cold; yet, the clinical evidence is mixed. To date, vitamin C intervention trials have not systematically recorded cold symptoms daily or looked at fluctuations in plasma histamine over an extended period. Also, trials have not been conducted in individuals with marginal vitamin C status. This study examined the impact of vitamin C supplementation during cold season on specific cold symptoms in a population with low plasma vitamin C concentrations. Healthy young males who were not regular smokers or training for competitive sports between the ages of 18 and 35 with below average plasma vitamin C concentrations were stratified by age, body mass index, and vitamin C status into two groups: VTC (500 mg vitamin C capsule ingested twice daily) or CON (placebo capsule ingested twice daily). Participants were instructed to fill out the validated Wisconsin Upper Respiratory Symptom Survey-21 daily for 8 weeks. Blood was sampled at trial weeks 0, 4, and 8. Plasma vitamin C concentrations were significantly different by groups at study week 4 and 8. Plasma histamine decreased 4.2% in the VTC group and increased 17.4% in the CON group between study weeks 0 and 8, but these differences were not statistically significant (p>0.05). Total cold symptom scores averaged 43±15 for the VTC group compared to 148±36 for the CON group, a 244% increase in symptoms for CON participants versus VTC participants (p=0.014). Additionally, recorded symptom severity and functional impairment scores were lower in the VCT group than the CON group (p=0.031 and 0.058, respectively). Global perception of sickness was 65% lower in the VTC group compared to the CON group (p=0.022). These results suggest that 1000 mg of vitamin C in a divided dose daily may lower common cold symptoms, cold symptom severity, and the perception of sickness. More research is needed to corroborate these findings.
ContributorsOsterday, Gillean (Author) / Johnston, Carol (Thesis advisor) / Beezhold, Bonnie (Committee member) / Vaughan, Linda (Committee member) / Arizona State University (Publisher)
Created2012
Description
It has been well established that mitochondria play a critical role in the pathology of Friedreich's Ataxia. This disease is believed to be caused by a deficiency of frataxin, which research suggests is responsible for iron sulfur cluster assembly. This incomplete assembly of iron sulfur clusters is believed to be linked with dysfunctional complexes in the mitochondrial respiratory chain, increased oxidative stress, and potential cell death. Increased understanding of the pathophysiology of this disease has enabled the development of various therapeutic strategies aimed at restoring mitochondrial respiration. This thesis contains an analysis of the biological activity of several classes of antioxidants against oxidative stress induced by diethyl maleate in Friedreich's Ataxia lymphocytes and CEM leukemia cells. Analogues of vitamin E α-tocopherol have been shown to protect cells under oxidative stress. However, these same analogues show various levels of inhibition towards the electron transport chain complex I. Bicyclic pyridinols containing a ten carbon substituent provided favorable cytoprotection. N-hydroxy-4-pyridone compounds were observed to provide little protection. Similarly, analogues of CoQ10 in the form of pyridinol and pyrimidinol compounds also preserved cell viability at low concentrations.
ContributorsJaruvangsanti, Jennifer (Author) / Hecht, Sidney (Thesis advisor) / Woodbury, Neal (Committee member) / Skibo, Edward (Committee member) / Arizona State University (Publisher)
Created2012
Description
Mitochondria produce the majority portion of ATP required in eukaryotic cells. ATP is generated through a process known as oxidative phosphorylation, through an pathway consisting five multi subunit proteins (complex I-IV and ATP synthase), embedded inside the mitochondrial membrane. Mitochondrial electron transport chain dysfunction increases reactive oxygen species in the cell and causes several serious disorders. Described herein are the synthesis of antioxidant molecules to reduce the effects in an already dysfunctional system. Also described is the study of the mitochondrial electron transport chain to understand the mechanism of action of a library of antioxidants. Illustrated in chapter 1 is the general history of research on mitochondrial dysfunction and reported ways to ameliorate them. Chapter 2 describes the design and synthesis of a series of compounds closely resembling the redox-active quinone core of the natural product geldanamycin. Geldanamycin has been reported to confer cytoprotection to FRDA lymphocytes in a dose dependent manner under conditions of induced oxidative stress. A library of rationally designed derivatives has been synthesized as a part of our pursuit of a better neuroprotective drug. Chapter 3 describes the design and synthesis of a library of pyrimidinol analogues. Compounds of this type have demonstrated the ability to quench reactive oxygen species and sustain mitochondrial membrane potential. Described herein are our efforts to increase their metabolic stability and total ATP production. It is crucial to understand the nature of interaction between a potential drug molecule and the mitochondrial electron transport chain to enable the design and synthesis a better therapeutic candidates. Chapter 4 describes a part of the enzymatic
binding studies between a molecular library synthesized in our laboratory and the mitochondrial electron transport chain using sub mitochondrial particles (SMP).
binding studies between a molecular library synthesized in our laboratory and the mitochondrial electron transport chain using sub mitochondrial particles (SMP).
ContributorsDey, Sriloy (Author) / Hecht, Sidney M. (Thesis advisor) / Angell, Charles A (Committee member) / Gould, Ian (Committee member) / Arizona State University (Publisher)
Created2015
Description
The energy required in a eukaryotic cell is provided by mitochondria. Mitochondrial electron transport chain (ETC) coupled with oxidative phosphorylation generates ATP. During electron transport, electron leakage from the ETC produces reactive oxygen species (ROS). In healthy cells, there are preventive and defense mechanisms in place to manage ROS. Maintaining a steady balance of ROS is very important because overproduction of ROS can lead to several pathological conditions. There are several strategies to prevent ROS production. Addition of external antioxidants is widely used among them. Discussed in the first part of Chapter 1 is the mitochondrial ETC, ROS production and antioxidant strategies.
The second part of Chapter 1 is concerned with ribosomal protein synthesis in bacteria. Ribosome, the organelle that synthesizes proteins with exceptional fidelity, has a strong bias for α-L-amino acids. It has been demonstrated that reengineering of the peptidyltransferase center (PTC) of the ribosome could enable the incorporation of both α-D-amino acids and β-amino acids into full length protein.
Oxidative stress is a common cause of various neurological disorders such as Alzheimer’s disease and Parkinson’s disease. Antioxidative strategies are used widely for the treatment of these disorders. Although several antioxidants demonstrated positive results in vitro as well as in in vivo models, none of them have been effective in clinical settings. Hence, there is an ongoing search for effective neuroprotective drugs. Described in Chapter 2 is the synthesis and biological evaluation of several methylene blue analogues as potentially effective antioxidants for the treatment of pathologies related to oxidative stress.
In Chapter 3, the synthesis and ribosomal incorporation of several rationally designed dipeptidomimetic analogues are discussed. The dipeptidomimetic analogues are structurally similar to the GFP chromophore and, therefore, highly fluorescent. In addition, the backbone of the dipeptidomimetic analogues resemble the peptide backbone of a dipeptide, due to which they can be incorporated into protein by modified ribosomes selected for the incorporation of dipeptides.
Discussed in Chapter 4 is the synthesis of the pdCpA derivatives of several β-amino acids. The pdCpA derivatives were ligated to tRNA-COH and were used as probes for studying the regio- and stereoselectivity of modified ribosomes.
The second part of Chapter 1 is concerned with ribosomal protein synthesis in bacteria. Ribosome, the organelle that synthesizes proteins with exceptional fidelity, has a strong bias for α-L-amino acids. It has been demonstrated that reengineering of the peptidyltransferase center (PTC) of the ribosome could enable the incorporation of both α-D-amino acids and β-amino acids into full length protein.
Oxidative stress is a common cause of various neurological disorders such as Alzheimer’s disease and Parkinson’s disease. Antioxidative strategies are used widely for the treatment of these disorders. Although several antioxidants demonstrated positive results in vitro as well as in in vivo models, none of them have been effective in clinical settings. Hence, there is an ongoing search for effective neuroprotective drugs. Described in Chapter 2 is the synthesis and biological evaluation of several methylene blue analogues as potentially effective antioxidants for the treatment of pathologies related to oxidative stress.
In Chapter 3, the synthesis and ribosomal incorporation of several rationally designed dipeptidomimetic analogues are discussed. The dipeptidomimetic analogues are structurally similar to the GFP chromophore and, therefore, highly fluorescent. In addition, the backbone of the dipeptidomimetic analogues resemble the peptide backbone of a dipeptide, due to which they can be incorporated into protein by modified ribosomes selected for the incorporation of dipeptides.
Discussed in Chapter 4 is the synthesis of the pdCpA derivatives of several β-amino acids. The pdCpA derivatives were ligated to tRNA-COH and were used as probes for studying the regio- and stereoselectivity of modified ribosomes.
ContributorsRoy Chowdhury, Sandipan (Author) / Hecht, Sidney (Thesis advisor) / Gould, Ian (Committee member) / Gust, John Devens (Committee member) / Arizona State University (Publisher)
Created2016
Description
Birds have shown promise as models of diabetes due to health and longevity despite naturally high plasma glucose concentrations, a condition which in diabetic humans leads to protein glycation and various complications. Research into mechanisms that protect birds from high plasma glucose have shown that some species of birds have naturally low levels of protein glycation. Some hypothesize a diet rich in carotenoids and other antioxidants protects birds from protein glycation and oxidative damage. There is little research, however, into the amount of protein glycation in birds of prey, which consume a high protein, high fat diet. No studies have examined the potential link between the diet of carnivorous birds and protein glycation. The overall purpose of this study was to evaluate whether birds of prey have higher protein glycation given their high protein, high fat diet in comparison to chickens, which consume a diet higher in carbohydrates. This was accomplished through analyses of serum samples from select birds of prey (bald eagle, red-tailed hawk, barred owl, great horned owl). Serum samples were obtained from The Raptor Center at the University of Minnesota where the birds of prey consumed high protein, high fat, non-supplemented diets that consisted of small animals and very little to no carbohydrate. Serum was also obtained from one chicken for a control, which consumed a higher carbohydrate and antioxidant-rich diet. Glucose, native albumin glycation and antioxidant concentrations (uric acid, vitamin E, retinol and several carotenoids) of each sample was measured. Statistical analyses showed significant between group differences in percent protein glycation amongst the birds of prey species. Glycation was significantly higher (p < 0.001) in bald eagles (23.67 ± 1.90%) and barred owls (24.28 ± 1.43%) compared to red-tailed hawks (14.31 ± 0.63%). Percent glycation was higher in all birds of prey compared to the chicken sample and literature values for chicken albumin glycation. Levels of the carotenoid lutein were significantly higher in bald eagles and barred owls compared to great horned owls and red-tailed hawks and the carotenoids beta-cryptoxanthin and beta-carotene were significantly greater in bald eagles compared to red-tailed hawks and great horned owls.
ContributorsIngram, Tana (Author) / Sweazea, Karen (Thesis advisor) / Johnston, Carol (Committee member) / Lespron, Christy (Committee member) / Arizona State University (Publisher)
Created2017
Description
Healthy mitochondria are essential for cell survival. Described herein is the synthesis of a family of novel aminoquinone antioxidants designed to alleviate oxidative stress and prevent the impairment of cellular function. In addition, a library of bleomycin disaccharide analogues has also been synthesized to better probe the tumor targeting properties of bleomycin. The first study involves the synthesis of a benzoquinone natural product and analogues that closely resemble the redox core of the natural product geldanamycin. The synthesized 5-amino-3-tridecyl-1,4-benzoquinone antioxidants were tested for their ability to protect Friedreich's ataxia (FRDA) lymphocytes from induced oxidative stress. Some of the analogues synthesized conferred cytoprotection in a dose-dependent manner in FRDA lymphocytes at micromolar concentrations. The biological assays suggest that the modification of the 2-hydroxyl and N-(3-carboxypropyl) groups in the natural product can improve its antioxidant activity and significantly enhance its ability to protect mitochondrial function under conditions of oxidative stress. The second project focused on the synthesis of a library of bleomycin disaccharide-dye conjugates and monitored their cellular uptake by fluorescence microscopy. The studies reveal that the position of the carbamoyl group plays an important role in modulating the cellular uptake of the disaccharide. It also led to the discovery of novel disaccharides with improved tumor selectivity.
ContributorsMathilakathu Madathil, Manikandadas (Author) / Hecht, Sidney M. (Thesis advisor) / Rose, Seth (Committee member) / Woodbury, Neal (Committee member) / Arizona State University (Publisher)
Created2013