An Exploration of Cross-dehydrogenative Coupling Methodology and The Synthesis of Transient Receptor Potential Melastatin Member 8 (TRPM8) Channel Modulators

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atmire.migration.oldid5300
dc.contributor.advisorDerksen, Darren
dc.contributor.authorLeGay, Christina
dc.contributor.committeememberBack, Thomas
dc.contributor.committeememberSutherland, Todd
dc.contributor.committeememberRo, Dae-Kyun
dc.date.accessioned2017-02-02T17:21:08Z
dc.date.available2017-02-02T17:21:08Z
dc.date.issued2017
dc.date.submitted2017en
dc.description.abstractStructure-activity relationship (SAR) studies of natural product analogues that modulate transient receptor potential (TRP) channels have been a useful tool for the development of potent and selective channel modulators. TRP channels play numerous physiological roles, including temperature and pain sensation, and have emerged as viable therapeutic targets. Recently, the Derksen group produced a library of TRP melastatin member 8 (TRPM8) channel modulators based on the natural product menthol. The first library of menthol analogues was prepared via an optimized and cost-effective synthetic route from commercially available starting materials. The biological evaluation of the first library revealed three novel TRPM8 channel modulators: an agonist with an EC50 of 11 ± 1 μM, an antagonist with an IC50 of 2 ± 1 μM, and an allosteric modulator that boosted the channel response towards consecutive applications of menthol. This thesis describes the results of the first library, and the tailoring of established synthetic methods to prepare a second generation library of natural product analogues based on the TRPM8 antagonist from the first library. Also described is the exploration of the organo-mediated cross-dehydrogenative coupling (CDC) of silyl enol ether and ketone substrates with the goal of preparing aldol adducts, which are key moieties in bioactive compounds including TRP channel modulators. CDC was employed for the direct functionalization of carbon-hydrogen bonds to prepare aldol adducts in an effort to overcome the issues of controlling reactivity and selectivity in aldol addition reactions. This thesis describes the variety of substrates and reaction conditions screened, and the measurements and calculations conducted in an attempt to optimally produce aldol like adducts directly from silyl protected alcohols. The highest yield achieved was an 18% GC-MS yield despite considerable effort and exploration of the reaction mechanism.en_US
dc.identifier.citationLeGay, C. (2017). An Exploration of Cross-dehydrogenative Coupling Methodology and The Synthesis of Transient Receptor Potential Melastatin Member 8 (TRPM8) Channel Modulators (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/24889en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/24889
dc.identifier.urihttp://hdl.handle.net/11023/3635
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectChemistry
dc.subjectChemistry--Organic
dc.subjectChemistry--Pharmaceutical
dc.subject.otherTRPM8
dc.subject.otherorganic synthesis
dc.subject.otherNatural products
dc.subject.otherTRP modulators
dc.subject.otheroxidative cross-dehydrogenative coupling
dc.titleAn Exploration of Cross-dehydrogenative Coupling Methodology and The Synthesis of Transient Receptor Potential Melastatin Member 8 (TRPM8) Channel Modulators
dc.typemaster thesis
thesis.degree.disciplineChemistry
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameMaster of Science (MSc)
ucalgary.item.requestcopytrue
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