Development of New N-Cyclopropyl Based Electron Transfer Probes for Cytochrome P-450 and Monoamine Oxidase Catalyzed Reactions

Grimm, Michelle L.

Development of New N-Cyclopropyl Based Electron Transfer Probes for Cytochrome P-450 and Monoamine Oxidase Catalyzed Reactions

dc.contributor.author	Grimm, Michelle L.	en
dc.contributor.committeechair	Tanko, James M.	en
dc.contributor.committeemember	Castagnoli, Neal Jr.	en
dc.contributor.committeemember	Mahaney, James M.	en
dc.contributor.committeemember	Buchanan, J. Paige	en
dc.contributor.department	Chemistry	en
dc.date.accessioned	2014-03-14T21:11:40Z	en
dc.date.adate	2011-05-26	en
dc.date.available	2014-03-14T21:11:40Z	en
dc.date.issued	2011-05-04	en
dc.date.rdate	2011-05-26	en
dc.date.sdate	2011-05-25	en
dc.description.abstract	The recent upsurge of degenerative diseases believed to be the result of oxidative stress has sparked an increased interest in utilizing the fundamental principles of physical organic chemistry to understand biological problems. Enzyme pathways can pose several experimental complications due to their complexity, therefore the small molecule probe approach can be utilized in an attempt understand the more complex enzyme mechanisms. The work described in this dissertation focuses on the use of N-cyclopropyl amines that have been used as probes to study the mechanism of monoamine oxidase (MAO) and cytochrome P-450 (cP-450). A photochemical model study of benzophenone triplet (3BP) with the MAO-B substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and two of its derivatives, 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine and (+/-)-[trans-2-phenylcyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine is presented in Chapter 2. The barrier for ring opening of aminyl radical cations derived from N-cyclopropyl derivatives of tertiary amines (such as MPTP) is expected to be low. Reactions of 3BP with all three compounds are very similar. The results suggest that the reaction between benzophenone triplet and tertiary aliphatic amines proceed via a simple hydrogen atom transfer reaction. Additionally these model examinations provide evidence that oxidations of N-cyclopropyl derivatives of MPTP catalyzed by MAO-B may not be consistent with a pure SET pathway. The chemistry of N-cyclopropyl amines has been used to study the mechanism of amine oxidations by cP-450. Until recently, the rate constant for these ring opening reactions has not been reported. Direct electrochemical examinations of N-cyclopropyl-N-methylaniline showed that the radical cation undergoes a unimolecular rearrangement consistent with a cyclopropyl ring opening reaction. Examination of both the direct and indirect electrochemical data showed that the oxidation potential N-cyclopropyl-N-methylaniline to be +0.528 V (0.1 M Ag⁺/Ag), and rate constant for ring opening of 4.1 x 10⁴ s⁻¹. These results are best explained by two phenomena: (i) a resonance effect in which the spin and charge of the radical cation in the ring closed form is delocalized into the benzene ring hindering the overall rate of the ring opening reaction, and/or (ii) the lowest energy conformation of the molecule does not meet the stereoelectronic requirements for a ring opening pathway. Therefore a new series of spiro cyclopropanes were designed to lock the cyclopropyl group into the appropriate bisected conformation. The electrochemical results reported herein show that the rate constant for ring opening of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] are 3.5 x 10² s⁻¹ and 4.1 x 10² s⁻¹ with redox potentials of 0.3 V and 0.366 V respectively. In order to examine a potential resonance effect a derivative of N-methyl-N-cyclopropylaniline was synthesized to provide a driving force for the ring opening reaction thereby accelerating the overall rate of the ring opening pathway. The electrochemical results show that the rate constant for ring opening of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline to be 1.7 x 10⁸ s⁻¹ . The formal oxidation potential (E°OX) of this substrate was determined to be 0.53 V. The lowered redox potentials of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] can be directly attributed to the electron donating character of the ortho alkyl group of the quinoline base structure of these spiro derivatives, and therefore the relative energy of the ring closed radical cations directly affects the rate of ring opening reactions. The relief of ring strain coupled with the formation of the highly resonance stabilized benzylic radical explains the rate increase for the ring opening reaction of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline.	en
dc.description.degree	Ph. D.	en
dc.identifier.other	etd-05252011-083050	en
dc.identifier.sourceurl	http://scholar.lib.vt.edu/theses/available/etd-05252011-083050/	en
dc.identifier.uri	http://hdl.handle.net/10919/37919	en
dc.publisher	Virginia Tech	en
dc.relation.haspart	Grimm_ML_D_2011.pdf	en
dc.relation.haspart	Grimm_ML_D_2011_Copyright.pdf	en
dc.relation.haspart	Grimm_ML_D_copywrite2.pdf	en
dc.rights	In Copyright	en
dc.rights.uri	http://rightsstatements.org/vocab/InC/1.0/	en
dc.subject	Cyclopropane ring opening	en
dc.subject	Radical cation	en
dc.subject	Cyclopropyl amines	en
dc.subject	Hydrogen atom transfer	en
dc.subject	Single electron transfer	en
dc.title	Development of New N-Cyclopropyl Based Electron Transfer Probes for Cytochrome P-450 and Monoamine Oxidase Catalyzed Reactions	en
dc.type	Dissertation	en
thesis.degree.discipline	Chemistry	en
thesis.degree.grantor	Virginia Polytechnic Institute and State University	en
thesis.degree.level	doctoral	en
thesis.degree.name	Ph. D.	en