NITROGEN OXIDE RELEASING PRODRUGS AS ANTIINFLAMMATORY, ANTICANCER AND CARDIOPROTECTIVE AGENTS

Persistent Link:
http://hdl.handle.net/10150/145745
Title:
NITROGEN OXIDE RELEASING PRODRUGS AS ANTIINFLAMMATORY, ANTICANCER AND CARDIOPROTECTIVE AGENTS
Author:
Basudhar, Debashree
Issue Date:
2011
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:
Embargo: Release after 10/14/2011
Abstract:
This dissertation focuses on chemical and biological evaluation of diazeniumdiolate based nitrogen oxide releasing prodrugs. Three projects are described. i. Synthesis and biological evaluation of a series of new nitroxyl (HNO) releasing non-steroidal antiinflammatory drugs (NSAIDs) and comparison to related nitric oxide (NO) releasing NSAIDs A series of HNO releasing isopropylamine-based diazeniumdiolate adducts of NSAIDs and the NO releasing diethylamine diazeniumdiolate counterpart were synthesized. The aspirin derivatives were evaluated for antiinflammatory, cardioprotective and anticancer effects. Both prodrugs demonstrated similar antiinflammatory properties to aspirin but significantly lower gastrointestinal ulceration, which is a common side effect of aspirin. The HNO adduct also improved cardiac contractility. The chemotherapeutic potential of the prodrugs was assessed in vitro and in vivo. Both the prodrugs inhibited growth of cultured carcinoma cells without inducing cytotoxicity towards non-tumorogenic cell lines. The higher cytotoxicity of the HNO adduct was in part due to increased production of reactive nitrogen and oxygen species leading to oxidative damage to DNA, inhibition of glyceraldehydes-3-phosphate dehydrogenase and upregulation of signaling pathways leading to caspase-3 mediated induction of apoptosis. The NO adduct is a promising candidate for reduction of metastasis by increasing E-cadherin levels, which influences cellular adhesion. Both derivatives showed significantly reduced angiogenesis in cultured cells and tumor volume in nude mice. ii. Synthesis and characterization of primary amine based cyclic amine diazeniumdiolates and comparison to their acetoxy methyl ester derivatives. A series of HNO releasing cyclic amine diazeniumdiolates were synthesized to expand upon the few examples of primary amine diazeniumdiolates. An ester derivative of cyclopentylamine NONOate was also synthesized, to increase decomposition half-life and to improve HNO production and better cellular uptake. This modification increased its cytotoxicity compared to ionic NONOates. iii. Evaluation of mechanism of action of JS-K. JS-K (O²-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)-piperazin-1-yl]-diazeniumdiolate) has previously been found to be highly cytotoxic in many cancer cell lines compared to ionic diazeniumdiolates. Thus, the role of NO in cytotoxicity of JS-K was explored. A low intracellular NO flux in combination with a lack of any effect on cyclic guanosine monophosphate (cGMP) dependent pathway suggests that NO is not directly responsible for the cytotoxicity of JS-K.
Type:
text; Electronic Dissertation
Keywords:
aspirin; cancer; Cyclooxygenase; Nitric oxide; Nitroxyl; NSAID
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
Miranda, Katrina M.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleNITROGEN OXIDE RELEASING PRODRUGS AS ANTIINFLAMMATORY, ANTICANCER AND CARDIOPROTECTIVE AGENTSen_US
dc.creatorBasudhar, Debashreeen_US
dc.contributor.authorBasudhar, Debashreeen_US
dc.date.issued2011en
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.releaseEmbargo: Release after 10/14/2011en_US
dc.description.abstractThis dissertation focuses on chemical and biological evaluation of diazeniumdiolate based nitrogen oxide releasing prodrugs. Three projects are described. i. Synthesis and biological evaluation of a series of new nitroxyl (HNO) releasing non-steroidal antiinflammatory drugs (NSAIDs) and comparison to related nitric oxide (NO) releasing NSAIDs A series of HNO releasing isopropylamine-based diazeniumdiolate adducts of NSAIDs and the NO releasing diethylamine diazeniumdiolate counterpart were synthesized. The aspirin derivatives were evaluated for antiinflammatory, cardioprotective and anticancer effects. Both prodrugs demonstrated similar antiinflammatory properties to aspirin but significantly lower gastrointestinal ulceration, which is a common side effect of aspirin. The HNO adduct also improved cardiac contractility. The chemotherapeutic potential of the prodrugs was assessed in vitro and in vivo. Both the prodrugs inhibited growth of cultured carcinoma cells without inducing cytotoxicity towards non-tumorogenic cell lines. The higher cytotoxicity of the HNO adduct was in part due to increased production of reactive nitrogen and oxygen species leading to oxidative damage to DNA, inhibition of glyceraldehydes-3-phosphate dehydrogenase and upregulation of signaling pathways leading to caspase-3 mediated induction of apoptosis. The NO adduct is a promising candidate for reduction of metastasis by increasing E-cadherin levels, which influences cellular adhesion. Both derivatives showed significantly reduced angiogenesis in cultured cells and tumor volume in nude mice. ii. Synthesis and characterization of primary amine based cyclic amine diazeniumdiolates and comparison to their acetoxy methyl ester derivatives. A series of HNO releasing cyclic amine diazeniumdiolates were synthesized to expand upon the few examples of primary amine diazeniumdiolates. An ester derivative of cyclopentylamine NONOate was also synthesized, to increase decomposition half-life and to improve HNO production and better cellular uptake. This modification increased its cytotoxicity compared to ionic NONOates. iii. Evaluation of mechanism of action of JS-K. JS-K (O²-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)-piperazin-1-yl]-diazeniumdiolate) has previously been found to be highly cytotoxic in many cancer cell lines compared to ionic diazeniumdiolates. Thus, the role of NO in cytotoxicity of JS-K was explored. A low intracellular NO flux in combination with a lack of any effect on cyclic guanosine monophosphate (cGMP) dependent pathway suggests that NO is not directly responsible for the cytotoxicity of JS-K.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectaspirinen_US
dc.subjectcanceren_US
dc.subjectCyclooxygenaseen_US
dc.subjectNitric oxideen_US
dc.subjectNitroxylen_US
dc.subjectNSAIDen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMiranda, Katrina M.en_US
dc.contributor.committeememberWalker, Annen_US
dc.contributor.committeememberGlass, Richarden_US
dc.contributor.committeememberChristie, Hamishen_US
dc.contributor.committeememberEnemark, Johnen_US
dc.identifier.proquest11596en
dc.identifier.oclc752261457en
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