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Investigating the Chemical Space and Metabolic Bioactivation of Natural Products and Cross-Reactivity of Chemical Inhibitors in Cyp450 Phenotyping

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Investigating the Chemical Space and Metabolic Bioactivation of Natural Products and Cross-Reactivity of Chemical Inhibitors in Cyp450 Phenotyping INVESTIGATING THE CHEMICAL SPACE AND METABOLIC BIOACTIVATION OF NATURAL PRODUCTS AND CROSS-REACTIVITY OF CHEMICAL INHIBITORS IN CYP450 PHENOTYPING Nicholas M. Njuguna Supervisor: Prof. Kelly Chibale Department of Chemistry, University of CapeTown Town Co-supervisor: Dr. Collen Masimirembwa African Institute of Biomedical Science andCape Technology, Harare, Zimbabwe of Thesis presented for the Degree of Doctor of Philosophy In the Department of Chemistry UniversityUNIVERSITY OF CAPE TOWN November 2014 The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non- commercial research purposes only. Published by the University of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. Univeristy of Cape Town DECLARATION I, Nicholas Mwaura Njuguna, hereby declare that: (i) This thesis is my own unaided work, both in conception and execution, and that apart from the normal guidance of my supervisors; I have received no assistance apart from that acknowledged; (ii) Neither the substance nor any part of the thesis has been submitted in the past, or is to be submitted for a Degree in the University of Cape Town or any other University. Signed: Date: i DEDICATION To my family: Dad, Mum, Kim, Maureen, Joe and Shi For your enduring love, steadfast support and unshakeable belief that have made my journey into the unknown so much more bearable. ii ACKNOWLEDGEMENTS I wish to convey my heartfelt gratitude to all the people that contributed in every way, great or small, in the conceptualisation, execution and conclusion of this work. To my supervisor, Prof. Kelly Chibale: no words in the English language (or any other) can truly express the eternal gratitude and boundless appreciation I have for granting me the opportunity to work under your guidance. Your exceptional scientific mentorship, great vision, unrelenting work ethic, generosity, and humility are a true inspiration. Ahsante sana! To my co-supervisor, the indefatigable Dr. Collen Masimirembwa, who taught me everything I know about drug metabolism, a bit about tae kwondo and lots more besides, I extend my heartfelt thanks and utmost admiration. I shall always cherish the unforgettable time I spent working on my project at AiBST and the unbelievable warmth of our hosts in Zimbabwe. Shukran sensei Collen! Past and present members of the Medicinal Chemistry and H3-D Research Groups, too numerous to mention here, from whom I received invaluable advice, assistance, support and genuine friendship throughout my time in Cape Town. Special thanks go to Ms. Elaine Rutherfoord-Jones, for her amazing organizational skills, warm spirit and generous heart - truly the ‘glue’ that binds our research group so covalently together. I also wish to wholeheartedly acknowledge Novartis Pharma AG for their sponsorship to participate in the once-in-a-lifetime experience 2013 Novartis Next Generation Scientist Program in Basel, Switzerland. Particular thanks go to our mentors from the Novartis D&I Team: Drs. Colin Pillay, Fareed Mirza, Marcello Gutierrez, Henri-Michelle Yere, Rita Michelle and Isabella Alberini. Special thanks also go to my scientific mentors at the Novartis DMPK Department: Dr. Gian Camenisch, Dr. Kenichi Umehara, Marc Witschi and Claire Juif. iii I also wish to gratefully acknowledge Prof. Peter J. Smith and Dr. Lubbe Weisner at the UCT Department of Pharmacology for unfettered access to their laboratory facilities and especially their expert advice on LC-MS instrumentation and experimentation. To Pete Roberts and Gianpiero Benincasa, many thanks for your technical assistance in the characterisation of compounds using NMR and MS. To the South African Medical Research Council, National Research Foundation and the Novartis Research Foundation, I convey my heartfelt appreciation for generously funding my studies. Finally and most important, my eternal gratitude goes to our Heavenly Father God, for mercifully granting me the health, strength and perseverance to see this through. iv ABSTRACT Natural products have been exploited by humans as the most consistently reliable source of medicines for hundreds of years. Owing to the great diversity in chemical scaffolds they encompass, these compounds provide an almost limitless starting point for the discovery and development of novel semi-synthetic or wholly synthetic drugs. In Africa, and many other parts of the world, natural products in the form of herbal remedies are still used as primary therapeutic interventions by populations far removed from conventional healthcare facilities. However, unlike conventional drugs that typically undergo extensive safety studies during development, traditional remedies are often not subjected to similar evaluation and could therefore harbour unforeseen risks alongside their established efficacy. A comparison of the ‘drug-like properties’ of 335 natural products from medicinal plants reported in the African Herbal Pharmacopoeia with those of 608 compounds from the British Pharmacopoeia 2009 was performed using in silico tools. The data obtained showed that the natural products differed significantly from conventional drugs with regard to molecular weight, rotatable bonds and H-bond donor distributions but not with regard to lipophilicity (cLogP) and H-bond acceptor distributions. In general, the natural products were found to exhibit a higher degree of deviation from Lipinski’s ‘Rule-of-Five’. Additionally, these compounds possessed a slightly greater number of structural alerts per molecule compared to conventional drugs, suggesting a higher likelihood of undergoing metabolic bioactivation. A combination of CYP450 enzyme inactivation assays and reactive metabolite trapping experiments was used to evaluate in vitro bioactivation of 15 natural product and natural product-derived compounds. Gedunin, Justicidin A and Jamaicin were found to be potent inhibitors of the main drug metabolizing isoform CYP3A4. Gedunin also exhibited potent inhibition of CYP2C19. The inhibition of CYP3A4 was, however, not time-dependent and therefore unlikely to be due to reactive metabolite-mediated inactivation of the enzyme. Inhibition of the other v main drug metabolizing isoforms, CYP1A2, CYP2C9 and CYP2C19 was markedly less pronounced. Direct assessment of the formation of electrophilic reactive metabolites was carried out by incubating 11 of the 15 compounds in hepatic microsomal preparations fortified with nucleophilic trapping agents. Using methoxylamine as a trapping agent, incubations of the monosubstituted furan ring-containing compounds Gedunin and the tetraol DC3 were found to contain components strongly suspected to be trapped reactive metabolites. None of the compounds tested formed detectable adducts when incubated in the presence of either reduced glutathione or potassium cyanide. The cross-reactivity of eight chemical inhibitors commonly used in early CYP450 phenotyping assays revealed the relatively low selectivity of ticlopidine and diethyldithiocarbamate. These assays also highlighted the particularly low potency of diethylthiocarbamate as the routinely preferred inhibitor for determining the contribution of hepatic CYP2E1 to xenobiotic metabolism. The data obtained provided ample evidence for the need to identify and characterise a superior replacement inhibitor for CYP2E1 phenotyping. The determined cross-reactivity values of different inhibitors were used to formulate a mathematical strategy to compensate for cross-inhibition in CYP450 enzyme phenotyping calculations. Recalculation of previously obtained CYP3A4 phenotyping data using the new strategy appeared to improve the correlation between fm,CYP3A4 values determined using different phenotyping approaches. A similar effect on phenotyping data from other CYP450 enzymes could not be established owing to a limitation in the size of the pre-existing dataset. vi LIST OF ABBREVIATIONS AND SYMBOLS °C Degrees Celsius µg Microgram µM Micromolar Å Angstrӧm ACE Angiotensin converting enzyme ADMET Absorption, distribution, metabolism, excretion and toxicology AHP African Herbal Pharmacopoeia AKR Aldo-keto reductase enzyme AO Aldehyde oxidase APCI Atmospheric pressure chemical ionization BFC 7-Benzyloxy-4-(trifluoromethyl)coumarin BP British Pharmacopoeia CDCl3 Deuterated chloroform cDNA Complementary DNA CEC 3-Cyano-7-ethoxycoumarin cLogP Calculated water-octanol partition coefficient CLPG Calopogonium isoflavone A CNL Constant neutral loss CNS Central Nervous System COMT Catechol-O-methyl transferase enzyme COX Cyclooxygenase enzyme CQ-R Chloroquine resistant CQ-S Chloroquine sensitive CSIR Council for Scientific and Industrial Research (South Africa) CUC-A Cucurbitacin A CUC-B Cucurbitacin B CUC-C Cucurbitacin C CYP450 Cytochrome P450 Enzyme Da Daltons DC14 Leoleorin A vii DETC Diethyldithiocarbamate DMF Dimethylformamide DMPK Drug metabolism and pharmacokinetics DMSO Dimethylsulfoxide DNA Deoxyribonucleic acid EMA European Medicines Agency EMS Enhanced mass spectrum EPI Enhanced product ion ESI Electro-spray ionisation FDA (United States) Food and Drug Administration fm,CYP Fraction of substrate metabolized by CYP450 enzyme FMO Flavin-containing monoxygenase FMTN Formononetin FSDA Fusidic acid GB Gigabytes GEDN Gedunin GHz Gigahertz GIT Gastro-intestinal tract GSH Reduced glutathione GST Glutathione transferase enzyme HCOOH Formic acid HCOONH4 Ammonium formate HLM Human liver microsomes
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