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- All Subjects: electron transport
- Creators: Hecht, Sidney M.
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
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