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Harnessing the Power of P450 Enzymes Aaron T. Larsen

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Harnessing the Power of P450 Enzymes Aaron T. Larsen Harnessing the Power of P450 Enzymes A Chemical Auxiliary-Based Approach to Predictable P450 Oxidations at Inactivated C-H Bonds Aaron T. Larsen A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy Department of Chemistry McGill University Montreal, Quebec, Canada H3A 2K6 Submitted: November, 2011 © Aaron T. Larsen, 2011 Abstract Abstract Enantioselective hydroxylation of one specific methylene in the presence of many similar groups is debatably the most challenging chemical transformation. Although chemists have recently made progress towards the hydroxylation of inactivated C-H bonds, enzymes like P450s (CYPs) remain unsurpassed in specificity and scope. The substrate promiscuity of many P450s is desirable for synthetic applications; however, the inability to predict the products of these enzymatic reactions and the poor activity and stability of these enzymes is impeding advancement. In chapter 2 of this thesis, we evaluate several strategies to improve the activity and stability of CYP3A4. These strategies include the immobilization of CYP3A4 inside molecular hydrogels and silica in addition to the chemical modification of CYP3A4 using various anhydrides. Although none of the strategies we investigate here greatly enhance the catalytic utility of the enzyme, CYP3A4 is shown to be highly tolerant to functionalization at a large number of surface residues and to the presence of extremely high concentrations of silica during catalysis. Recognizing the potential for enzymes containing small, hydrophobic active sites to catalyze Diels-Alder reactions, chapter 3 describes the design and application of several assays to evaluate the Diels-Alderase activity of CYP2E1. Although the presence of CYP2E1 is not found to increase the rates of the reactions we investigate here, the results do demonstrate that there is ii Abstract an interaction between one or more of the substrates and the enzyme at either the active site or at another binding pocket. In chapter 4, we evaluate 4 auxiliaries for their ability to direct CYP3A4 oxidations. When linked to substrates, several of these auxiliaries are shown to direct CYP3A4 oxidations at specific C-H bonds. Although the auxiliaries we explore here are found to be limited in utility, several important lessons are learned which we apply to the design of a next generation auxiliary to be discussed in the following chapter. In chapter 5, we demonstrate the utility of theobromine as a chemical auxiliary to control the selectivity of CYP3A4 reactions. When linked to substrates, inexpensive, achiral theobromine directs the reaction to produce hydroxylation or epoxidation at the fourth carbon from the auxiliary with pro-R facial selectivity. This strategy provides a versatile yet controllable system for regio-, chemo- and stereo-selective oxidations at inactivated C-H bonds and establishes the utility of directing auxiliaries to mediate the activity of highly promiscuous enzymes. Recognizing the importance of product recovery, chapter 6 evaluates molecularly imprinted polymers for the selective purification of theobromine-containing molecules. When used for the solid-phase extraction, these materials allow for the near complete recovery of theobromine-containing products and starting materials from biocatalytic mixtures. This strategy represents an easily-tailored, effective, and reusable method of improving the recovered yield of theobromine-directed CYP3A4 oxidations. iii Résumé Résumé L’hydroxylation énantiosélective d'un méthylène spécifique en présence de nombreux autres groupes semblables est défendablement la transformation chimique la plus difficile. Bien que les chimistes aient récemment fait du progrès vers l'hydroxylation de liaisons C-H inactivées, il existe des enzymes comme les cytochromes P450 (CYP) qui demeurent inégalées par rapport à leur spécificité et leur portée. La promiscuité de substrat démontré par plusieurs P450 est souhaitable pour certaines applications de synthèse, mais une prévisibilité des produits difficiles, en plus de leur faible activité et stabilité empêchent l'avancement dans ce domaine. Dans le chapitre 2 de cette thèse, nous évaluons plusieurs stratégies pour améliorer l'activité et la stabilité de CYP3A4. Ces stratégies comprennent son immobilisation à l'intérieur d’hydrogels moléculaire et de silice, en plus de sa modification chimique avec une variété d’anhydrides. Bien qu'aucunes des stratégies étudiées ici n’aient grandement amélioré l'utilité catalytique de l'enzyme, elles démontrent quand-même que CYP3A4 est très tolérantes envers la fonctionnalisation d’un grand nombre de ses résidus de surface et à la présence de concentrations extrêmement élevées de silice pendant la catalyse. Reconnaissant le potentiel des enzymes possédant de petits sites actifs hydrophobes de catalyser des réactions Diels-Alder, chapitre 3 décrit la conception et l'application de plusieurs tests pour évaluer l'activité Diels-Alderase de CYP2E1. Bien que la présence de CYP2E1 n’a pas augmenter le taux des réactions étudiées ici, les résultats démontrent qu'il existe une interaction entre un ou plusieurs des substrats et l'enzyme, soit au site actif ou à un autre poche de liaison. iv Résumé Dans le chapitre 4, nous évaluons quatre auxiliaires pour leur capacité de diriger des oxydations par CYP3A4. Quand ils sont reliés à des substrats, nous avons trouvé que plusieurs de ces auxiliaires dirigent les oxydations par CYP3A4 à des liaisons C-H spécifiques. Bien que les auxiliaires explorés ici se trouvent à être limitées dans leur utilité, nous avons appris plusieurs leçons importantes que nous avons appliqué envers la conception d'une nouvelle génération d’auxiliaires à être discutés dans le chapitre suivant. Dans le chapitre 5, nous démontrons l'utilité de la théobromine en tant qu’auxiliaires chimique pour contrôler la sélectivité des réactions du CYP3A4. Quand il est relié à des substrats peu coûteux, la théobromine achiral dirige la réaction, donnant naissance à des produits hydroxylés ou époxydés au niveau du quatrième carbone à partir de l'auxiliaire avec une sélectivité faciale pro-R. Cette stratégie fournit un système versatile et contrôlable offrant des produits oxydés de façon regio-, chimio- et stéréo-sélective à des liaisons CH inactivé. Elle démontre aussi l'utilité des auxiliaires par rapport à leur habileté de contrôler l'activité des enzymes hautement promiscues. Reconnaissant l'importance de la récupération du produit, le chapitre 6 évalue des polymères à empreintes moléculaires pour la purification sélective de molécules contenant la théobromine. Quand ils sont utilisés pour l'extraction en phase solide, ces matériaux permettent la récupération quasi-complète de produits et de substrats contenant la théobromine à partir de mélanges biocatalytiques. Cette stratégie représente une méthode adaptable, efficace et réutilisable permettant d'améliorer le rendement récupéré des produits d’oxydations dirigée par la théobromine. v Acknowledgements Acknowledgements I would like to thank: My parents for granting me support and independence; my brother, Leif, for always looking up to me; Kelly Livesley for her patience; Dr. Michael Eze for taking a chance on me; Dr. Désirée Vanderwel for making me love enzymes; Dr. Kayode Akinnusi for teaching me how to be a synthetic chemist; Amélie Ménard for more useful discussion than can be remembered; Erin May for helping me make the breakthrough; Dr. Lee Frieburger for testing the waters before me; Vanja Polic for being the ideal protégé; Dr. Faisal Aldaye for his continued kindness and inspiration; Nadim Saaed for preferring me; Dr. Eric Therrien for tolerating my questions; Omar Zahr for deactivating the lethargy field; Siqi Zhu for brightening the lab; Dr. Karine Auclair for teaching me what it takes to be a great professor and adviser; and Mandy Slávik for being my best friend. vi Table of Contents Table of Contents Abstract…………………………………………………………………………………...…….ii Résumé………………………………………………………………………………………....iv Acknowledgements………………………………………………………………………….…vi Table of Contents………………………………………………………………………...…....vii List of Figures……………………………………………………………………………….…xv List of Schemes…………………………….………………………………………………..…xx List of Tables……………………………………………………………………………….….xxi Abbreviations……………………………………………………………………………..…..xxii References………………………………………………………………………………….…204 Select NMR spectra………………………………………………………………………………... Select HPLC spectra……………………………………………………………………………….. Chapter 1: P450 enzymes and biocatalysis 1.1 Biocatalysis.............................................................................................................................2 1.1.1 A case for biocatalysis……………………………..…………………………..…..2 1.1.2 Biocatalysis: an overview………………………………………………………….4 1.1.3 Advantages of biocatalysis…………………………………………………….......5 1.1.4 Techniques to improve existing biocatalysts…………...……………………….....7 1.2 P450 enzymes……………………………………………………………………………….8 1.2.1 P450 structural characteristics……………………………………………………..8 vii Table of Contents 1.3 P450 catalytic mechanism………………………………………………………………...13 1.4 P450-catalyzed reactions…………………………………………..……………………...15 1.4.1 P450 catalyzed hydrocarbon hydroxylation……………………………………...15 1.4.2 P450-catalyzed hydroxylations of aromatic rings……………………………..…17 1.4.3 P450-catalyzed oxidation of heteroatoms……………………………………......18 1.4.4 P450-catalyzed epoxidation……………………………………………………...20 1.5 Chemical catalysts currently used for inactivated C-H bond oxidation…………….....22
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