No description available.

Universiẗat, Diss., 1990--Heidelberg.

Zugl.: Wien, Techn. University, Diss., 1997.

The flavin-containing monoamine oxidases (MAO) A and B catalyze the oxidative deamination of primary and secondary amines. The overall process involves a two electron oxidation of the amine to the iminium with concomitantreduction of the flavin. Based on extensive studies with a variety of chemical probes, Silverman and colleagues have proposed a catalytic pathway for the processing of amine substrates and inactivators by MAO-B that is initiated by a single electron transfer (SET) step from the nitrogen lone pair to the oxidized flavin followed by α-proton loss from the resulting amine radical cation that leads to a carbon radical. Subsequent transfer of the second electron leads to the reduced flavin and the iminium product. In the case of N-cyclopropylamines, the initially formed amine radical cation is proposed to undergo rapid ring opening to form a highly reactive primary carbon centered radical that is thought to be responsible for inactivation of the enzyme. In this thesis we have exploited the unique substrate and inactivator properties of 1,4-disubstituted tetrahydropyridine derivatives to probe the mechanism of MAO-B catalysis. Reports of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a structurally unique substrate of MAO-B initiated these studies. Consistent with the SET pathway, the N-cyclopropyl analog of MPTP proved to be an efficient time and concentration dependent inactivator but not a substrate of MAO-B. On the other hand, the 4-benzyl-1-cyclopropyl analog is both a substrate and inactivator of MAO-B. These properties may not be consistent with the obligatory formation of a cyclopropylaminyl radicalcation intermediate. In an attempt to gain further insight into the mechanism associated with the MAO catalyzed oxidation of 1,4-disubstituted tetrahydropyridines, deuterium isotope effects studies on both the substrate and inactivation properties of the 4-benzyl-1- cyclopropyl derivative were undertaken. A series of 1-methyl- and 1-cyclopropyltetrahydropyridine derivatives bearing various heteroaro-matic groups at C-4 also have been examined. The MAO-B substrate properties, inactivator properties and partition ratios for these compounds together with preliminary results from chemical model studies are discussed in terms of the MAO-B catalytic pathway. / Ph. D.

Reductive electron transfer has been successfully utilized to facilitate the first enantioselective desymmetrisation of malonate derivatives. Selective monoreduction of cyclic 1,3-diesters through the combined use of SmI2-Et3N and chiral non-racemic diols has granted rapid access to enantioenriched β-hydroxy acids containing challenging quaternary centres – an abundant motif in many drug molecules. Unique radical anions generated from the single electron reduction of cyclic 1,3-diesters have been exploited in cyclisation cascades. Capture of acyl-type radical anions by both alkene and alkyne acceptors have permitted the construction of complex bicyclic architectures in a single synthetic operation. The reductive cyclisation cascade of lactones has also been demonstrated, using SmI2-H2O to achieve a challenging domino 5-exo-trig/6-exo-trig cyclisation event. This process generates highly decorated carbo[5.4.0]bicyclic scaffolds with complete diastereocontrol.

The MAO-B catalyzed metabolic bioactivation of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to generate the neurotoxic 1-methyl-4-phenylpyridinium species (MPP+) is well documented. The N-cyclopropyl analog (CPTP) of MPTP is a mechanism based inactivator of MAO-B which presumably is processed by a single electron transfer (SET) pathway to generate a bioalkylating species. These results have prompted us to study how the cytochromes P450, the major liver drug metabolizing oxidases, interact with N-cyclopropyl analogs of MPTP. HPLC with diode array detection and LC-electrosprary ionization mass spectrometry (LC-ESI/MS) based methods have been developed for metabolite detection and characterization. From the UV spectral data and pseudomolecular ion species observed by LC-ESI/MS, we have identified N-oxide, C-hydroxylated, and pyridinium metabolites. For the trans-1-(2-phenylcyclopropyl) analog, cinnamaldehyde and p-hydroxycinnamaldehyde also were characterized. Incubation of CPTP and its derivatives with cDNA expressed human hepatic cytochrome P450 has shown that CYP2D6 catalyzes the formation of cinnamaldehyde, the N-descyclopropyl, pyridinium and hydroxylated products. CYP3A4 is responsible for the formation of the N-descyclopropyl and pyridinium species and cinnamaldehyde but it does not mediate any hydroxylation reactions. Since both the a-carbon oxidation and N-descyclopropylation transformations are mediated by a single enzyme (either CYP2D6 or CYP3A4), we propose a common intermediate for both pathways, namely the cyclopropylaminyl radical cation generated by the SET pathway. This intermediate partitions between the a-carbon oxidation pathway leading to the dihydropyridinium and pyridinium species and the ring opening pathway leading to the N-descyclopropyl metabolite and aldehyde species. The phenyl substituent on the cyclopropyl ring stabilizes the ring opened distonic radical cation and favors the ring opening pathway and results in the formation of less of the pyridinium species. The proton and methyl substituents on the cyclopropyl ring favor the a-carbon oxidation pathway and increased amounts of the pyridinium species are formed. / Master of Science

The chemistry of the radical anion generated from 1,I-dimethyl-5,7-di-tbutylspiro[ 2,5]octa-4,7-dien-6-one (<b>20</b>) was studied electrochemically using cyclic and linear sweep voltammetry (CV, LSV). The reduction potential of <b>20</b> was estimated to be -2.5 V VS. 0.1 M Ag⁺/Ag, similar to the reduction potentials observed for aryl ketones and enones. LSV results for the reduction of <b>20</b> are consistent with the occurrence of substrate reduction followed by a subsequent chemical step (an EC mechanism). The broadness of the reduction wave and variation of peak potential with sweep rate suggest that the rate limiting step is heterogeneous electron transfer. Ring opening of the radical anion generated from <b>20</b> results in a 9:1 ratio of the 3° and 1° distonic radical anions. The rate constant for ring opening has been estimated to be k ≥ 10⁷s⁻¹ with a calculated (AM1) enthalpy of ring opening of ΔH° > -15 kcal/mol. The facile nature of radical anion ring opening can be ascribed to the relief of cyclopropyl ring strain in conjunction with the establishment of aromaticity. On this basis, the regiochemistry of the ring opening of the radical anion derived from <b>20</b> suggests that polar and SET pathways can be differentiated based upon the regiospecificity of cyclopropyl ring opening. In reactions between <b>20</b> and nucleophiles known to react via SET with carbonyl compounds, 20 successfully produced products characteristic of SET pathways. However, subsequent studies of the reaction between <b>20</b> and thiophenoxide, a nucleophile purported to undergo SET, produced no evidence for a SET pathway. It was discovered that ring opened products may also be formed by competing polar pathways involving a carbocationic intermediate, especially in protic solvents. In dipolar aprotic solvents, ring opening occurs primarily via an S_N2 process, with nucleophilic attack occurring preferentially at the least hindered carbon. The strengths and weaknesses of <b>20</b> as a SET probe are discussed / Ph. D.

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. / Ph. D.

Flavin adenine dinucleotide (FAD) is a coenzyme that participates in the redox process of flavoenzymes. Attempts to characterize the catalytic pathways of these enzymes have relied in part on the use of FAD chemical models. The efforts described in this dissertation focus on the chemical model approach to investigate the mechanism of the monoamine oxidase (MAO) catalyzed oxidation of the cyclic tertiary allylamine 1-methyl-4-(2-methyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (TMMP), which is a close analog of the parkinsonian-inducing designer drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MAO-B catalyzes the conversion of MPTP and its derivatives into active neurotoxins in the brain that subsequently mediate neurogenerative processes that mimic the events leading to idiopathic Parkinson\'s disease. Monoamine oxidase inhibitors are currently used to treat early stages of Parkinson\'s disease. Two FAD chemical models are examined in this project: 5-ethyl-3-methyllumiflavinium perchlorate (5Et3MLF+ClO4-) and 3-methyllumiflavin (3MLF). The flavinium salt 5Et3MLF+ClO4- is an activated form of 3MLF. These FAD chemical models have been used to examine the MAO catalyzed oxidation. MAO-B is expressed in the brain and is known to be involved in the conversion of TMMP into the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MMP+). MAO-B is responsible for the alpha-carbon oxidation of TMMP to yield 1-methyl-4-(2-methylpyrrol-2-yl)-2,3-dihydropyridinium (DHP+), which then undergoes a second 2-electron oxidation to MMP+. Previous findings demonstrated that 3MLF and 5Et3MLF+ClO4- promoted the oxidation reaction of primary and secondary amines but not tertiary amines. However, the cyclic tertiary allylamine TMMP has not been examined experimentally. Therefore, the alpha-carbon oxidation of TMMP in the presence of the FAD chemical models is reported in this dissertation. The effect of dioxygen and water on the activity of these FAD models is also investigated. / Ph. D.

Ce travail s’inscrit dans la recherche de nouveaux 5-nitroimidazoles fonctionnalisés à visée thérapeutique. L’étude de la réactivité du 4-bromo-1,2-diméthyl-5-nitro-1H-imidazole vis-à-vis des réactions de couplages de Suzuki, Sonogashira et Stille a permis la synthèse de nouveaux 5-nitroimidazoles substitués en position 4. Par ailleurs, un couplage de Suzuki régiosélectif a pu être mis au point sur le 2,4-dibromo-1-méthyl-5-nitro-1H-imidazole permettant l’accès en une seule étape à des composés substitués à la fois en positions 2 et 4. Parmi les composés synthétisés via ces couplages pallado-catalysés, les dérivés chlorométhylés conjugués avec le groupement nitro ont été utilisés en tant que substrats pour l’étude de réactions par transfert monoélectronique (SRN1, TDAE). Ainsi, dans une seconde partie, nous décrivons la réaction entre le 4-(3-chloroprop-1-ynyl)-1,2-diméthyl-5-nitro-1H-imidazole et plusieurs anions nitronates dans des conditions de SRN1. Cette réactivité a pu être étendue au 2,4-bis(3-chloroprop-1-ynyl)-1-méthyl-5-nitro-1H-imidazole permettant la réalisation d’une bis-SRN1. La méthodologie TDAE a été mise en œuvre sur le 4-(3-chloroprop-1-ynyl)-1,2-diméthyl-5-nitro-1H-imidazole, avec de faibles rendements observés, contrairement à ceux obtenus avec le (E)-4-[4- (chlorométhyl)styryl]-1,2-diméthyl-5-nitro-1H-imidazole sur lequel plusieurs types d’électrophile ont pu être additionnés. Enfin, le pouvoir mutagène, ainsi que le potentiel de réduction des 5-nitroimidazoles synthétisés ont été déterminés. L’évaluation anti-infectieuse est actuellement en cours sur des souches de Giardia lamblia et sur une grande variété de bactéries anaérobies strictes. / This work focuses on the synthesis of novel functionalized 5-nitroimidazoles possessing therapeutic activities. New 4-substituted-5-nitroimidazoles were obtained using Suzuki, Stille or Sonogashira cross-coupling using the 4-bromo-1,2 dimethyl-5-nitro-1H-imidazole. Moreover, access to functionalized products at both 2 and 4 positions of imidazole ring was developed thanks to a regioselective Suzuki cross-coupling on the 2,4-dibromo-1-methyl-5-nitro-1H-imidazole. Among cross-coupling products, those possessing chloromethyle substituent conjugated with the nitro group, were employed as starting material in the single electron transfer reaction (SRN1, TDAE) studies. Therefore, in a second part, we described the reaction between the 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole and several nitronate anions in SRN1 conditions. This reactivity was applied to the 2,4-bis(3-chloroprop-1-ynyl)-1-méthyl-5-nitro-1H-imidazole allowing the formation of bis-SRN1 products. TDAE methodology was implemented on the 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole, however poor yields were observed. TDAE strategy on the (E)-4-[4-(chlorométhyl)styryl]-1,2-diméthyl-5-nitro-1H-imidazole were more successful, addition products with different electrophilic species were obtained. Finally, mutagenic power and potential of reduction of synthesized 5-nitroimidazole were assayed. The anti-infective properties of these novel 5-nitroimidazole are currently under investigation.