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- All Subjects: Chemistry
- Genre: Doctoral Dissertation
- Creators: Hecht, Sidney M.
- Member of: ASU Electronic Theses and Dissertations
- Resource Type: Text
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 ability to manipulate the interaction between small molecules and biological macromolecules towards the study of disease pathogenesis has become a very important part of research towards treatment options for various diseases. The work described here shows both the use of DNA oligonucleotides as carriers for a nicotine hapten small molecule, and the use of microsomes to study the stability of compounds derived to treat mitochondrial diseases.
Nicotine addiction is a worldwide epidemic because nicotine is one of the most widely used addictive substances. It is linked to early death, typically in the form of heart or lung disease. A new vaccine conjugate against nicotine held within a DNA tetrahedron delivery system has been studied. For this purpose, several strands of DNA, conjugated with a modified dTpT having three or six carbon atom alkynyl linkers, have been synthesized. These strands have later been conjugated to three separate hapten small molecules to analyze which conjugates formed would be optimal for further testing in vivo.
Mitochondrial diseases are hard to treat, given that there are so many different variations to treat. There is no one compound that can treat all mitochondrial and neurodegenerative diseases; however, improvements can be made to compounds currently under study to improve the conditions of those afflicted. A significant issue leading to compounds failing in clinical trials is insufficient metabolic stability. Many compounds have good biological activity, but once introduced to an animal, are not stable enough to have any effect. Here, several synthesized compounds have been evaluated for metabolic stability, and several showed improved stability, while maintaining biological activity.
Nicotine addiction is a worldwide epidemic because nicotine is one of the most widely used addictive substances. It is linked to early death, typically in the form of heart or lung disease. A new vaccine conjugate against nicotine held within a DNA tetrahedron delivery system has been studied. For this purpose, several strands of DNA, conjugated with a modified dTpT having three or six carbon atom alkynyl linkers, have been synthesized. These strands have later been conjugated to three separate hapten small molecules to analyze which conjugates formed would be optimal for further testing in vivo.
Mitochondrial diseases are hard to treat, given that there are so many different variations to treat. There is no one compound that can treat all mitochondrial and neurodegenerative diseases; however, improvements can be made to compounds currently under study to improve the conditions of those afflicted. A significant issue leading to compounds failing in clinical trials is insufficient metabolic stability. Many compounds have good biological activity, but once introduced to an animal, are not stable enough to have any effect. Here, several synthesized compounds have been evaluated for metabolic stability, and several showed improved stability, while maintaining biological activity.
ContributorsSchmierer, Margaret (Author) / Hecht, Sidney M. (Thesis advisor) / Allen, James (Committee member) / Gould, Ian (Committee member) / Arizona State University (Publisher)
Created2016
Description
The manipulation of biological targets using synthetic compounds has been the focal point of medicinal chemistry. The work described herein centers on the synthesis of organic small molecules that act either as probes for studying protein conformational changes or DNA–protein interaction, or as multifunctional radical quenchers.
Fluorescent labeling is of paramount importance to biological studies of proteins. For the development of new extrinsic small fluorophores, a series of tryptophan analogues has been designed and synthesized. Their pdCpA derivatives have been synthesized for tRNA activation and in vitro protein synthesis. The photophysical properties of the tryptophan (Trp) analogues have been examined, some of which can be selectively monitored even in the presence of multiple native tryptophan residues. Further, some of the Trp analogues form efficient FRET pairs with acceptors such as acridon-2-ylalanine (Acd) or L-(7-hydroxycoumarin-4-yl)ethylglycine (HCO) for the selective study of conformational changes in proteins.
Molecules which can bind with high sequence selectivity to a chosen target in a gene sequence are of interest for the development of gene therapy, diagnostic devices for genetic analysis, and as molecular tools for nucleic acid manipulations. Stereoselective synthesis of different alanyl nucleobase amino acids is described. Their pdCpA derivatives have been synthesized for tRNA activation and site-specific incorporation into the DNA-binding protein RRM1 of hnRNP LL. It is proposed that the nucleobase moieties in the protein may specifically recognize base sequence in the i-motif DNA through H-bonding and base-stacking interactions.
The mitochondrial respiratory chain accumulates more oxidative damage than any other organelle within the cell. Dysfunction of this organelle is believed to drive the progression of many diseases, thus mitochondria are an important potential drug target. Reactive oxygen species (ROS) are generated when electrons from the respiratory chain escape and interact with oxygen. ROS can react with proteins, lipids or DNA causing cell death. For the development of effective neuroprotective drugs, a series of N-hydroxy-4-pyridones have been designed and synthesized as CoQ10 analogues. All the analogues synthesized were evaluated for their ability to quench lipid peroxidation and reactive oxygen species (ROS).
Fluorescent labeling is of paramount importance to biological studies of proteins. For the development of new extrinsic small fluorophores, a series of tryptophan analogues has been designed and synthesized. Their pdCpA derivatives have been synthesized for tRNA activation and in vitro protein synthesis. The photophysical properties of the tryptophan (Trp) analogues have been examined, some of which can be selectively monitored even in the presence of multiple native tryptophan residues. Further, some of the Trp analogues form efficient FRET pairs with acceptors such as acridon-2-ylalanine (Acd) or L-(7-hydroxycoumarin-4-yl)ethylglycine (HCO) for the selective study of conformational changes in proteins.
Molecules which can bind with high sequence selectivity to a chosen target in a gene sequence are of interest for the development of gene therapy, diagnostic devices for genetic analysis, and as molecular tools for nucleic acid manipulations. Stereoselective synthesis of different alanyl nucleobase amino acids is described. Their pdCpA derivatives have been synthesized for tRNA activation and site-specific incorporation into the DNA-binding protein RRM1 of hnRNP LL. It is proposed that the nucleobase moieties in the protein may specifically recognize base sequence in the i-motif DNA through H-bonding and base-stacking interactions.
The mitochondrial respiratory chain accumulates more oxidative damage than any other organelle within the cell. Dysfunction of this organelle is believed to drive the progression of many diseases, thus mitochondria are an important potential drug target. Reactive oxygen species (ROS) are generated when electrons from the respiratory chain escape and interact with oxygen. ROS can react with proteins, lipids or DNA causing cell death. For the development of effective neuroprotective drugs, a series of N-hydroxy-4-pyridones have been designed and synthesized as CoQ10 analogues. All the analogues synthesized were evaluated for their ability to quench lipid peroxidation and reactive oxygen species (ROS).
ContributorsTalukder, Poulami (Author) / Hecht, Sidney M. (Thesis advisor) / Woodbury, Neal (Committee member) / Gould, Ian (Committee member) / Arizona State University (Publisher)
Created2016
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
Description
ABSTRACT Manipulation of biological targets using synthetic or naturally occurring organic compounds has been the focal point of medicinal chemistry. The work described herein centers on the synthesis of organic small molecules that are targeted either to cell surface receptors, to the ribosomal catalytic center or to human immunodeficiency virus reverse transcriptase. Bleomycins (BLMs) are a family of naturally occurring glycopeptidic antitumor agents with an inherent selectivity towards cancer cells. DeglycoBLM, which lacks the sugar moiety of bleomycin, has much lower cytotoxicity in cellular assays. A recent study using microbbuble conjugates of BLM and deglycoBLM showed that BLM was able to selectively bind to breast cancer cells, whereas the deglyco analogue was unable to target either the cancer or normal cells. This prompted us to further investigate the role of the carbohydrate moiety in bleomycin. Fluorescent conjugates of BLM, deglycoBLM and the BLM carbohydrate were studied for their ability to target cancer cells. Work presented here describes the synthesis of the fluorescent carbohydrate conjugate. Cell culture assays showed that the sugar moiety was able to selectively target various cancer cells. A second conjugate was prepared to study the importance of the C-3 carbamoyl group present on the mannose residue of the carbohydrate. Three additional fluorescent probes were prepared to improve the uptake of this carbohydrate moiety into cancer cells. Encouraged by the results from the fluorescence experiments, the sugar moiety was conjugated to a cytotoxic molecule to selectively deliver this drug into cancer cells. The nonsense codon suppression technique has enabled researchers to site specifically incorporate noncanonical amino acids into proteins. The amino acids successfully incorporated this way are mostly α-L-amino acids. The non-α-L-amino acids are not utilized as substrates by ribosome catalytic center. Hoping that mutations near the ribosome peptidyltransferase site might alleviate its bias towards α-L-amino acids, a library of modified ribosomes was generated. Analogues of the naturally occurring antibiotic puromycin were used to select promising candidates that would allow incorporation of non-α-L-amino acids into proteins. Syntheses of three different puromycin analogues are described here. The reverse transcriptase enzyme from HIV-1 (HIV-1 RT) has been a popular target of HIV therapeutic agents due to its crucial role in viral replication. The 4-chlorophenyl hydrazone of mesoxalic acid (CPHM) was identified in a screen designed to find inhibitors of strand transfer reactions catalyzed by HIV-1 RT. Our collaborators designed several analogues of CPHM with different substituents on the aromatic ring using molecular docking simulations. Work presented here describes the synthesis of eight different analogues of CPHM.
ContributorsPaul, Rakesh (Author) / Hecht, Sidney M. (Thesis advisor) / Moore, Ana L (Committee member) / Rose, Seth D (Committee member) / Arizona State University (Publisher)
Created2013