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- All Subjects: Antioxidants
- Creators: Gould, Ian R
- Creators: Lespron, Christy
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
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
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