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dc.contributor.authorMelnychuk, Stephanieen
dc.date2008-09-12 13:09:42.427
dc.date.accessioned2008-09-15T20:33:46Z
dc.date.available2008-09-15T20:33:46Z
dc.date.issued2008-09-15T20:33:46Z
dc.identifier.urihttp://hdl.handle.net/1974/1432
dc.descriptionThesis (Master, Chemistry) -- Queen's University, 2008-09-12 13:09:42.427en
dc.description.abstractPhosphoryl transfer reactions are vital to life. In response to the slow intrinsic rates of phosphoryl transfer, Nature has evolved a series of enzymes designed to accelerate these reactions and allow them to occur at biologically relevant rates. These metallo-enzymes are largely characterized by bi- or tri-nuclear active sites with effective dielectric constants that more closely resemble those of organic solvents than water. This project was designed to better understand the mechanisms by which metallo-enzymes cleave phosphodiesters with poor leaving groups. The stability of the phosphodiester is central to the storage of genetic information in DNA and RNA. The cleavage of a series of more reactive RNA models, 2-hydroxylpropyl aryl phosphates 1a-g, catalyzed by a dinuclear Zn(II)2 complex of 53 in methanol was explored. A solution of 53:Zn(II)2:(-OCH3) was observed to accelerate the decomposition of 1a-g with rates that were 10^11-10^12-fold greater than the methoxidepromoted reaction at ss pH 9.47, approaching rate accelerations achieved by natural enzymes. The remarkable activity of 53:Zn(II)2:(-OCH3) and 36:Zn(II)2:(-OCH3) towards the cleavage of 1a-g probed the study of the decomposition of diribonucleotides(3'->€™ 5')UpU and (3'->€™ 5'€™)ApC in methanol. The 53:Zn(II)2:(-OCH3)- and 36:Zn(II)2:(-OCH3)-catalyzed decomposition of UpU achieved k2 values of 1.21 ± 0.17 and (7.04 ± 0.99) x 10^-2 M^-1s^-1. The reactivity of ApC in the presence of these systems was unimpressive, however Zn(II) ions in ethanol resulted in the isomerization of 3'->€™ 5'€™)ApC to (2'->™ 5'€™)ApC providing support for the existence of a pentacoordinate phosphorane intermediate. The pentacoordinate phosphorane was further explored through the reaction of 36:Zn(II)2:(-OCH3) with the cyclic phosphate 58 and 2-hydroxylpropyl methyl phosphate (59). In the presence of 36:Zn(II)2:(-OCH3) the rate of isomerization of 59/59a (kobs = (4.7 ± 0.5) x 10^-3 s^-1) exceeded that of expulsion of the methoxy group (kobs = 1.62 x 10^-3 s^-1), thus confirming the existence of a pentacoordinate phosphorane intermediate (60)and providing support for a two-step phosphodiester cleavage reaction. The catalytic efficiency of 36:Zn(II)2:(-OCH3) towards the cleavage of stable phosphodiesters probed its application towards the decomposition of dimethyl phosphate (2) in methanol-d4. The exchange of OCH3 for OCD3 occurred with kcatmax = (2.27 ± 0.03) x 10^-6 s^-1.en
dc.format.extent1122338 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectphosphodiestersen
dc.subjectmethanolen
dc.subjectdinuclear metal catalysisen
dc.titleA Mechanistic Study in Methanol: Cleavage of RNA Models and Highly Stable Phosphodiesters with Dinuclear Zn(II) Complexesen
dc.typethesisen
dc.description.degreeM.Sc.en
dc.contributor.supervisorBrown, Robert Stanleyen
dc.contributor.departmentChemistryen
dc.degree.grantorQueen's University at Kingstonen


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