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dc.contributor.advisorIlies, Marc A.
dc.creatorSanku, Rajesh Kishore kumar
dc.date.accessioned2020-11-05T15:01:51Z
dc.date.available2020-11-05T15:01:51Z
dc.date.issued2018
dc.identifier.urihttp://hdl.handle.net/20.500.12613/3522
dc.description.abstractCancer is the second most common cause of death in the world. One of the objectives of this thesis is to biologically evaluate a series of anti-cancer polymeric aromatic/heterocyclic bis-sulfonamides and pyridinium sulfonamides which were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores. Testing of these novel inhibitors and their precursors against a panel of membrane-bound CA isoforms, including tumor-overexpressed CA IX and XII and cytosolic isozymes, identified nanomolar-potent inhibitors against both classes and several compounds with medium isoform selectivity. In the case of pyridinium sulfonamides we used complexes of the inhibitors with cyclodextrins or sulfocalixarene to enhance aqueous solubility for biological testing. The ability of CA inhibitors to kill tumor cells overexpressing CA IX and XII was tested under normoxic and hypoxic conditions, using 2D and 3D in vitro cellular models. The study identified a nanomolar potent PEGylated bis-sulfonamide CA inhibitor (25), as well as cyclodextrin and sulfocalixarenes complexes, which were able to significantly reduce the viability of colon HT-29, breast MDA-MB231, and ovarian SKOV-3 cancer cell lines, thus revealing the potential of polymer conjugates in CA inhibition and cancer treatment. As a different disease state yet still a concern, cognitive dysfunction markedly impacts patients with a host of psychiatric conditions including attention deficit hyperactivity disorder, autism spectrum disorder, drug addiction, schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, and of course, Parkinson’s and Alzheimer’s diseases and other types of dementia. Another objective of this thesis was to profile several series of bis-imidazoles for physicochemical, in-vitro and in-vivo properties as potential memory and learning enhancers (nootropics). Biological testing on eight isozymes of carbonic anhydrase (CA) present in the human brain revealed compounds with nanomolar potency against at least one membrane bound, cytosolic or mitochondrial CA isozymes, combined with good physicochemical properties. We also identified lead compounds with the ability to rescue experimental animals from drug-induced memory deficits, using an optimized Novel Object Recognition Task (NORT) procedure.
dc.format.extent154 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectPharmaceutical Sciences
dc.subjectBehavioral Pharmacology
dc.subjectCancer Biology
dc.subjectCarbonic Anhydrase
dc.subjectDrug Screening
dc.subjectDurg Devlopment
dc.subjectLearning and Memory
dc.titleDEVELOPMENT AND BIOLOGICAL EVALUATION OF CARBONIC ANHYDRASE MODULATORS AS POTENTIAL NOOTROPICS AND ANTICANCER AGENTS
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberWalker, Ellen A.
dc.contributor.committeememberCanney, Daniel J.
dc.contributor.committeememberFassihi, Reza
dc.contributor.committeememberMesaros, A. Clementina
dc.description.departmentPharmaceutical Sciences
dc.relation.doihttp://dx.doi.org/10.34944/dspace/3504
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-11-05T15:01:51Z


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