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    Modification of fresh tissue surfaces; synthesis of labeled L-dopa analogs; and synthesis of metoclopramide analogs.

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    Date
    2006-05-27
    Author
    Perera, Aruna B.
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    Abstract
    One of the main goals of the primary project was to develop methods to site specifically immobilize functional proteins on a tissue surface. There are many examples of proteins that have been chemically modified and attached onto solid surfaces such as silica or gold. In those studies, proteins were chemically modified to introduce functional groups, and in most cases, the solid surface was also chemically modified to introduce functional groups onto its surface. The proteins were then immobilized onto the surface using a chemical ligation reaction. However, to the best of our knowledge there are no examples reported in literature where functional proteins have been covalently attached in a site specific fashion onto the surface of a fresh tissue. We hypothesized that the methods used for modifying and immobilizing biomolecules onto solid surfaces could be adapted for use on fresh tissue surfaces. Several different strategies were investigated for the immobilization of the model biomolecules. A direct alkylation method involved reacting a biotin or fluorescent marker (bearing an amine reactive species such as an active ester) directly to the –NH2 groups present on the tissue surface. Reductive methods involved the reduction of the tissue surface with a thiol reducing agent to give free sulfhydryl. The reduced tissue surface was then reacted with a protein or other molecule bearing a thiol reactive species. An oxidative technique used periodiate to oxidize geminal diols (such as those found in proteoglycans in the ECM of tissue) to carbonyl compounds. The oxidation was followed by the reaction of the tissue surface with nucleophilic reagents, such as hydrazides. Aromatic L-amino acid dercarboxylase (AADC) is an enzyme that converts 3, 4-dihydroxyphenylalanine (L-dopa) to dopamine and 5-hydroxytryptophan to serotonin. Inherited deficiency of this enzyme leads to decreased levels of these two neurotransmitters, resulting in severe early onset neurological disorders. In the absence of AADC activity, L-dopa is methylted to 3-0-methyl dopa which is then accumulated in blood, urine and cerebrospinal fluid in infants and children with a deficiency of this enzyme. 3-O-methyl dopa therefore, provides a biochemical marker that can be used to screen for this disease. Thus, the goals of the second project were to synthesize a labeled analog of 3-O-methyldopa for the use in mass spectrometry for the screening of AADC deficiency. The clinical usefulness of high dose MCA as a radio-and chemosensitizer is limited by its central nervous system (CNS) side effects. Primary side effects include drowsiness, acute extrapyramidal reactions, akathisia (generalized motor restlessness) and drug induced Parkinson. MCA has also been shown to increase irritability and anxiety. These CNS side effects are chemically related to the ortho-methoxy group in MCA, which planarizes the molecule and allows it to have a high affinity for dopamine D2 receptors. Since the ortho-methoxy group was suggested to be the cause of the CNS side effects, we hypothesized that modifications at the ortho-methoxy group could decrease the CNS side effects and increase cytotoxicity. Several derivatives of the O-substituted MCA were synthesized and their structure activity relationship (SAR) was studied.
    URI
    http://hdl.handle.net/2104/2998
    Department
    Chemistry and Biochemistry.
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    • Theses/Dissertations - Chemistry & Biochemistry

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    Copyright © Baylor® University All rights reserved. Legal Disclosures.
    Baylor University Waco, Texas 76798 1-800-BAYLOR-U
    Baylor University Libraries | One Bear Place #97148 | Waco, TX 76798-7148 | 254.710.2112 | Contact: libraryquestions@baylor.edu
    If you find any errors in content, please contact librarywebmaster@baylor.edu
    DSpace software copyright © 2002-2016  DuraSpace
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