Small Molecule Approaches Toward Therapeutics for Alzheimer's Disease and Colon Cancer

Persistent Link:
http://hdl.handle.net/10150/337213
Title:
Small Molecule Approaches Toward Therapeutics for Alzheimer's Disease and Colon Cancer
Author:
Smith, Breland Elise
Issue Date:
2014
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Embargo:
Dissertation not available (per author's request)
Abstract:
The research described in this dissertation is focused on the knowledge-based, often in silico assisted design, targeted synthesis, and biological evaluation of small molecules of interest for two translational medicinal chemistry projects. The first project (Part 1) is aimed at the identification of blood brain barrier (BBB) penetrable dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) inhibitors as a potential disease modifying approach to mitigate cognitive deficits associated with Alzheimer's neurodegeneration. Two major series with potent activity against DYRK1A were identified in addition to a number of other chemotype sub-series that also exhibit somewhat promising activity. Extensive profiling of active analogs revealed interesting biological activity and selectivity, which led to the identification of two analogs for in vivo studies and revealed new opportunities for further investigation into other kinase targets implicated in neurodegeneration and polypharmacological approaches. The second project (Part 2) is focused on the development of compounds that inhibit PGE₂ production, while not affecting cyclooxygenase (COX) activity, as a novel approach to treat cancer. Compounds were designed with the intention of inhibiting microsomal prostaglandin E₂ synthase-1 (mPGES-1); however, biological evaluation revealed phenotypically active compounds in a cell based assay with an unknown mechanism of action. Further profiling revealed promising anticancer activity in xenograft mouse models. In addition, PGE₂ has been implicated in an immune evasion mechanism of F. tularensis, a strain of bacteria that remains an exploitable threat in biowarfare, thus a small number of analogs were evaluated in a cell model of F. tularensis infection stimulated PGE₂ production.
Type:
text; Electronic Dissertation
Keywords:
Medicinal Chemistry; Structure Based Drug Design; Biochemistry; Drug Discovery and Development
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Biochemistry
Degree Grantor:
University of Arizona
Advisor:
Hulme, Christopher

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleSmall Molecule Approaches Toward Therapeutics for Alzheimer's Disease and Colon Canceren_US
dc.creatorSmith, Breland Eliseen_US
dc.contributor.authorSmith, Breland Eliseen_US
dc.date.issued2014en
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.releaseDissertation not available (per author's request)en_US
dc.description.abstractThe research described in this dissertation is focused on the knowledge-based, often in silico assisted design, targeted synthesis, and biological evaluation of small molecules of interest for two translational medicinal chemistry projects. The first project (Part 1) is aimed at the identification of blood brain barrier (BBB) penetrable dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) inhibitors as a potential disease modifying approach to mitigate cognitive deficits associated with Alzheimer's neurodegeneration. Two major series with potent activity against DYRK1A were identified in addition to a number of other chemotype sub-series that also exhibit somewhat promising activity. Extensive profiling of active analogs revealed interesting biological activity and selectivity, which led to the identification of two analogs for in vivo studies and revealed new opportunities for further investigation into other kinase targets implicated in neurodegeneration and polypharmacological approaches. The second project (Part 2) is focused on the development of compounds that inhibit PGE₂ production, while not affecting cyclooxygenase (COX) activity, as a novel approach to treat cancer. Compounds were designed with the intention of inhibiting microsomal prostaglandin E₂ synthase-1 (mPGES-1); however, biological evaluation revealed phenotypically active compounds in a cell based assay with an unknown mechanism of action. Further profiling revealed promising anticancer activity in xenograft mouse models. In addition, PGE₂ has been implicated in an immune evasion mechanism of F. tularensis, a strain of bacteria that remains an exploitable threat in biowarfare, thus a small number of analogs were evaluated in a cell model of F. tularensis infection stimulated PGE₂ production.en_US
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectMedicinal Chemistryen_US
dc.subjectStructure Based Drug Designen_US
dc.subjectBiochemistryen_US
dc.subjectDrug Discovery and Developmenten_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineBiochemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHulme, Christopheren_US
dc.contributor.committeememberHulme, Christopheren_US
dc.contributor.committeememberMontfort, Williamen_US
dc.contributor.committeememberChristie, Hamishen_US
dc.contributor.committeememberBandarian, Vaheen_US
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