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    Improving Blood Brain Barrier Permeation of Small Molecules Exhibiting Chemotherapeutic and Neuroprotective Effects

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    Issue Date
    2008-05-06
    Author
    Desino, Kelly Elizabeth
    Publisher
    University of Kansas
    Format
    171 pages
    Type
    Dissertation
    Degree Level
    PH.D.
    Discipline
    Pharmaceutical Chemistry
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    The blood brain barrier is the body's natural defense system for limiting the brain's exposure to potentially harmful xenobiotics. This barrier exists between the blood of the systemic circulation and the brain and is made up of brain endothelial cells which have tight junctions, reduced pinocytosis, minimal fenestration and increased expression of metabolizing enzymes and membrane transporters capable of efflux. Estimates predict that the blood brain barrier may be capable of limiting up to 98% of all drugs from entering the brain and is therefore a major obstacle in drug delivery. The research presented herein highlights several small molecules that possess chemotherapeutic and neuroprotective properties. These molecules also represent various strategies for improving blood brain barrier penetration. Derivatives of the microtubule stabilizing agent paclitaxel were investigated in which chemical modification was employed to reduce interaction with the efflux transporter P-glycoprotein, which is critical in limiting paclitaxel's entry into the brain. TH-237A, another microtubule stabilizing agent that is structurally very different from paclitaxel was also characterized and was shown to have excellent blood brain barrier penetration. Additionally, derivatives of the monoamine oxidase inhibitor tranylcypromine were explored that have fatty acid and lipoamino acid chains of varying length attached to improve blood brain barrier permeability. In order for these compounds to exert their mechanism of action as either chemotherapeutic or neuroprotective agents, they must be able to penetrate the blood brain barrier. The specific objective of this project was to explore various chemical approaches to improving blood brain barrier permeability using pharmacologically relevant molecules.
    URI
    http://hdl.handle.net/1808/3972
    Collections
    • Dissertations [3958]
    • Pharmaceutical Chemistry Dissertations and Theses [90]

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    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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