Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1423 Exploring Catalytic Tellurium- Based Antioxidants Synthesis and Evaluation JIA-FEI POON ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 ISBN 978-91-554-9684-5 UPPSALA urn:nbn:se:uu:diva-302475 2016 Dissertation presented at Uppsala University to be publicly examined in B41, BMC, Husargatan 3, Uppsala, Thursday, 27 October 2016 at 09:30 for the degree of Doctor of Philosophy. The examination will be conducted in English. Faculty examiner: John Murphy (University of Strathclyde ). Abstract Poon, J.-f. 2016. Exploring Catalytic Tellurium-Based Antioxidants. Synthesis and Evaluation. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1423. 72 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9684-5. This thesis is concerned with the synthesis and evaluation of various tellurium-based chain- breaking antioxidants. The purpose is to find novel regenerable compounds with improved radical-trapping capacity. In the first part of this work, we explore the possibilities to incorporate tellurium into tocopherols and aromatic amines. Overall, tocopherols carrying alkyltelluro groups are better radical-trapping agents than the corresponding sulfur- and selenium analogues. Among them, 7-octyltelluro δ-tocopherol showed a ca. 17-fold higher reactivity than recorded for α- tocopherol and much better regenerability. Even longer inhibition times were recorded for the corresponding bis(tocopheryl) tellurides. In the aromatic amine series, diphenyl amines carrying alkyltelluro groups were shown to function as efficient radical-quenchers capable of inhibiting peroxidation for 460 min in the presence of N-acetylcysteine. Thiol-consumption experiments suggested that the long inhibition times are due to efficient quenching of in-situ formed alkoxyl radicals in a solvent cage. In the second part of the thesis, we study how the antioxidant properties are affected by variations in the electron density at tellurium and the number of alkyltelluro substituents in the molecule. Evaluation of a series of aryltelluro phenols carrying electron donating and electron withdrawing groups in the para-position of the aryl moiety suggested that a high electron density at the heteroatom prolonged the inhibition time. Among alkyltelluro phenols, alkyltelluro resorcinols and bis(alkyltelluro) phenols, phenols carrying alkyltelluro groups in both ortho positions were superior when it comes to radical-trapping activity and regenerability. Keywords: antioxidant, tellurium, selenium, radical-trapping, chain-breaking, ROS, glutathione peroxidase, tocopherol, aromatic amine, oxidative stress Jia-fei Poon, Department of Chemistry - BMC, Organic Chemistry, Box 576, Uppsala University, SE-75123 Uppsala, Sweden. © Jia-fei Poon 2016 ISSN 1651-6214 ISBN 978-91-554-9684-5 urn:nbn:se:uu:diva-302475 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-302475) To my parents List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Singh, V. P.; Poon, J.; Engman, L. Catalytic Antioxidants: Re- generable Tellurium Analogues of Vitamin E. Org. Lett. 2013, 15, 6274–6277. II Poon, J.; Singh, V. P.; Yan, J.; Engman, L. Regenerable Antiox- idants–Introduction of Chalcogen Substituents into Tocopherol. Chem. Eur. J. 2015, 21, 2447–2457. III Poon, J.; Yan, J.; Gates, P.; Engman, L. Regenerable Radical- trapping Tellurobistocopherol Antioxidants, Manuscript (2016). IV Poon, J.; Yan, J.; Singh, V. P.; Gates, P.; Engman, L.; Alkyltel- luro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines. Chem. Eur. J. 2016, 32, 12891–12903. V Poon, J.; Singh, V. P.; Engman, L. In Search of Catalytic Anti- oxidants–(Alkyltelluro)phenols, (Alkyltelluro)resorcinols, and Bis(alkyltelluro)phenols. J. Org. Chem. 2013, 78, 6008–6015. Appendix: Supplementary material. Reprints were made with permission from the respective publishers. Publications not included in this thesis: VI Singh, V. P.; Poon, J.; Engman, L. Turning Pyridoxine into a Catalytic Chain-Breaking and Hydroperoxide-Decomposing Antioxidant. J. Org. Chem. 2013, 78, 1478–1487. VII Singh, V. P.; Poon, J.; Butcher, R.; Engman, L. Pyridoxine- Derived Organoselenium Compounds with Glutathione Peroxi- dase-Like and Chain-Breaking Antioxidant Activity. Chem. Eur. J. 2014, 20, 12563–12571. VIII Singh, V. P.; Poon, J.; Butcher, R.; Lu, X.; Mestres, G.; Karls- son Ott, M.; Engman, L. Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide. J. Org. Chem. 2015, 50, 7385–7395. IX Yan, J.; Poon, J.; Singh, V. P.; Gates, P.; Engman, L. Regener- able Thiophenolic Radical-Trapping Antioxidants. Org. Lett. 2015, 17, 6162–6165. X Kumar, S.; Yan, J.; Poon, J.; Singh, V. P.; Lu, X.; Karlsson Ott, M., Engman, L., Kumar, S. Multifunctional Antioxidants: Re- generable Radical-Trapping and Hydroperoxide-Decomposing Ebselenols. Angew. Chem. Int. Ed. 2016, 55, 3729–3733. XI Lu, X.; Mestres, G.; Singh, V. P.; Effati, P.; Poon, J.; Engman, L.; Karlsson Ott, M. Selenium- and Tellurium-Based Antioxi- dants for Modulating Inflammation and Osteoblastic Activity, Submitted manuscript (2016). XII Singh, V. P.; Poon, J.; Yan, J.; Lu, X.; Karlsson Ott, M.; Butch- er, R. J.; Gates, P.; Engman, L. Nitro-, Azo- and Amino Deri- vates of Ebselen. Synthesis, Structure and Cytoprotective Ef- fects, Manuscript (2016). Contribution Report The author wishes to clarify his contribution to the papers included in the thesis: I Participated significantly in the synthesis and evaluation exper- iments using the two-phase lipid peroxidation system. Contrib- uted to writing of the paper. II Performed a significant part of the synthesis and evaluation experiments using the two-phase lipid peroxidation system. Contributed to writing of the paper. III Contributed to the formulation of the research idea and partici- pated extensively in the synthetic work. Performed all evalua- tion experiments using the two-phase peroxidation system and all thiol-consumption experiments. Contributed to writing of the paper. IV Performed most of the synthetic work, evaluation experiments using the two-phase lipid peroxidation system and thiol- consumption studies. Contributed to writing of the paper. V Performed all the synthesis and evaluation experiments using the two-phase peroxidation system. Participated in the GPx- experiments. Contributed to writing of the paper. Appendix: Contributed to the formulation of the research idea and partici- pated extensively in the synthetic work. Performed most of the evaluation experiments using the two-phase peroxidation sys- tem and all thiol-consumption experiments. Contributed to writ- ing of the appendix. Contents 1. Introduction ................................................................................................. 1 1.1 Oxidation ........................................................................................... 1 1.1.1 Oxygen .......................................................................................... 1 1.1.2 Free Radicals ................................................................................ 2 1.1.3 Autoxidation ................................................................................. 3 1.1.4 Oxidative Stress ............................................................................ 5 1.2 Antioxidants ......................................................................................... 6 1.2.1 Preventive antioxidants ................................................................. 7 1.2.2 Chain-Breaking Antioxidants ....................................................... 8 1.3 Chalcogens ......................................................................................... 11 2. Antioxidant Design ................................................................................... 13 2.1 Perspectives on Chain-Breaking Antioxidants ................................... 13 2.1.1 Hydrogen-Atom Transfer ........................................................... 13 2.1.2 Criteria for effective antioxidants ............................................... 14 2.1.3 Stoichiometric factor .................................................................. 17 2.2 Perspectives on Preventive Antioxidants ........................................... 19 2.3 Towards Multifunctional and Regenerable Antioxidants ................... 21 2.3.1 Background ................................................................................. 21 2.3.2 Multifunctional Antioxidants ...................................................... 21 2.3.3 Regeneration ............................................................................... 22 2.3.4 Aim of the work .......................................................................... 23 3. Synthesis ................................................................................................... 25 3.1 Synthesis of Chalcogen-Containing Tocopherol Antioxidants (Papers I – III) .......................................................................................... 25 3.2 Synthesis of Tellurium-Containing Aromatic Amine Antioxidants (Paper IV) ................................................................................................. 29 3.3 Synthesis of Phenolic Antioxidants: Alkyltelluro Phenols, Alkyltelluro Resorcinols and bis(Alkyltelluro) Phenols (Paper V) .......... 35 3.4 Synthesis of Aryltelluro Phenol