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Drug Discovery, Design and Synthesis of Polycyclic Regulators of Cancer Cells and Nuclear Receptors: Phenazine 5,10-Dioxides and Oxysterols

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Drug Discovery, Design and Synthesis of Polycyclic Regulators of Cancer Cells and Nuclear Receptors: Phenazine 5,10-Dioxides and Oxysterols Drug Discovery, Design and Synthesis of Polycyclic Regulators of Cancer Cells and Nuclear Receptors: Phenazine 5,10-dioxides and Oxysterols Dissertation for the degree of Philosophiae Doctor By Elvar Örn Viktorsson Faculty of Mathematics and Natural Sciences University of Oslo 2017 © Elvar Örn Viktorsson, 2017 Series of dissertations submitted to the Faculty of Mathematics and Natural Sciences, University of Oslo No. 1893 ISSN 1501-7710 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Print production: Reprosentralen, University of Oslo. To my father, Viktor Daði Bóasson (24.08.1952-19.12.2012†) I II Acknowledgements The work presented in this thesis was carried out between autumn 2013 and spring 2017 at the Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo. Liver X receptors were the primary focus of attention from autumn 2013 until spring 2014 and thereafter, the scope was turned to phenazines until spring 2017. A six-week research period was undertaken in summer 2015 at University Claude Bernard Lyon 1, France. As the end of this four-year journey at the UiO’s School of Pharmacy seems to be drawing near, it is only appropriate to thank those who have contributed to this work in many ways. First of all, I would like to express my deepest gratitude to Prof. Pål Rongved, my main supervisor. First and foremost, for giving me the opportunity to take on this challenge and for placing your trust in me. All the exciting talks about chemistry, biology, guitar gear and life in general have been a great pleasure so far, and I hope we can continue to collaborate in the unseen future. A special gratitude to my good friend and colleague, Dr. Alexander H. Åstrand for all his input and all the good times. You are the one who helped me the most in the beginning, and for that I am grateful. I would like acknowledge the talented biologists at the University of Bergen. Prof. Lars Herfindal, Dr. Reidun Æsøy and Prof. Stein Ove Døskeland, for all their contribution to the phenazine part. Dr. Eili Tranheim Kase as well for the supervision and design of all biological evaluations performed in the Liver X receptor project, along with helpful discussions on LXR-related biology. Assoc. Prof. Tore Bonge-Hansen from the Department of Chemistry and Bendik Grøthe also deserve large credit for their important contributions to the phenazine project. Professor II Ørjan Samuelsen and Christopher Fröhlich are acknowledged for antimicrobial evaluations in Tromsø. I also wish to thank some other current and former colleagues and staff at the University of Oslo’s Department of Pharmaceutical chemistry, all of which have contributed to such a III motivating and fun place to work at: Christian, Geir, Renate, Karoline, Åsmund, Marius, Jørn, Anthony, Eirik, Vegard, Lisa, Anders, Jens, Trond, Bora, Martin H. and Peter. “Legemiddelkjemi Blastoff!” The department engineers, Iuliana Johansen and Anne Bjerke are also thanked for general lab support and Halvor Aandal as well for his important help with formalities and shipment of samples. The master degree candidates I´ve had the pleasure of supervising and work with; Sindre Støa and Rasha Haseeb. This work could probably not have been finished without funding from the following sources: A NOVO exploratory Pre Seed Grant no. 4462, a BIOTEK2021 program grant from the Norwegian research council, a grant from University of Oslo’s innovation fund in 2015, Norwegian PhD School of Pharmacy grant 2015 and last but not least, the School of pharmacy, University of Oslo for employing me. It also seems impossible not to mention Prof. Frode Rise and Dirk Petersen for maintaining an outstanding and an impressive NMR-facility. Prof. Carl Henrik Görbitz and Dr. Sigurd Øien- Ødegaard are also acknowledged for the X-ray crystallographic work related to this thesis. The people who helped me proof read this thesis deserve a special mention: Pål Rongved, Alexander Åstrand, Åsmund Kaupang, Eili Kase, Christian Schnaars, Geir Kildahl-Andersen, and Þorsteinn Viktorsson. Thank you all. Outermost gratitude to Guðrún Þorsteinsdóttir and Eva Viktorsdóttir for all the support and encouragement throughout my studies. And finally, my better half, Sigríður Ólafsdóttir. Thank you for always supporting me, and for moving with me to Oslo. Your care, love and patience have made this dream of mine come true. Oslo, June 25th, 2017 Elvar Örn Viktorsson IV Abstract The work presented in this thesis employed conventional structure-activity relationship studies to guide the rational design of compounds that target acute myeloid leukemia, infections caused by resistant bacteria and metabolic diseases such as atherosclerosis, diabetes mellitus type 2 and obesity. Recent literature concludes that the phenazine 5,10-dioxide natural product iodinin (5) targets human leukemic cells potently and selectively. In this study, we synthesized iodinin from commercially available reagents and used structure-activity relationship studies as a tool to rationally guide the design and discovery of new antileukemic agents. In this process, the known antibiotic myxin (8) was identified to be equally potent to- and as selective towards leukemic cells as iodinin. This finding enabled us to conclude that one of iodinin’s two phenol groups can be O-functionalized without any loss of cytotoxic potency at the same time the selectivity towards AML cells over healthy cells is preserved (Paper I). Furthermore, synthesis and biological evaluation of iodinin- and myxin prodrugs revealed carbamate side chains to be an advantageous functionality to attach to the phenolic function. These prodrugs displayed enhanced potency, solubility and more efficient cell membrane penetration compared to iodinin (Paper II). By altering the substitution patterns of the phenazine scaffold in positions 6, 7 and 8, we could identify 7,8-dihalogenated- and 7,8-dimethylated carbamate-functionalized phenazine 5,10-dioxides with considerably enhanced potency, compared to that of iodinin and myxin, while preserving the selectivity towards leukemic cells. Phenazine 5,10-dioxides were also tested against strains of both Gram-positive and -negative bacteria with different profiles of resistance to antibiotics used in the clinic. Results retrieved from these experiments revealed clear trends that can guide further development of phenazine 5,10-dioxides for use in the treatment of severe infections. We were also interested in targeting the transcriptional machinery of cells through the liver X nuclear receptors (LXRs). The LXRs play a crucial role in the metabolism and homeostasis of cholesterol, lipids, bile acids and carbohydrates. Therefore, their potential to serve as drug targets in the context of metabolic diseases is immense. Individual reports state that the natural oxysterol 22(R)-hydroxycholesterol (22RHC) and its unnatural synthetic epimer 22(S)-hydroxycholesterol (22SHC) can promote opposite V biological effects in terms of LXR-regulated gene expression. Through virtual screening, synthesis of analogues and biological evaluations that assessed the expression of key LXR target genes, we managed to identify two new leads that mimicked the activities of 22SHC. One compound (LXR11) was found to be very promising in vitro and was investigated further in rats (Paper III). This compound did however fail to provide the desired outcome in vivo, most likely due to pharmacokinetic problems, such as rapid metabolism in the rat’s gastrointestinal tract. SAR studies were also conducted in vitro, and involved the synthetic preparation of analogues with different functionalities in position 22 of the cholesterol scaffold. The results from this study gave an enhanced understanding of how LXR-regulated gene expression can be manipulated by synthetic transformations in position 22 of the cholesterol scaffold – the compound 22-ketocholesterol (22KCH) was found to upregulate the expression of ABCA1 selectively, rendering it a promising new lead compound for further anti- atherosclerotic evaluations (Paper IV). VI List of publications and patents Paper I Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives Viktorsson, E. Ö.; Grøthe, B. M.; Aesoy, R.; Sabir, M.; Snellingen, S.; Prandina, A.; Åstrand, O. A. H.; Bonge-Hansen, T.; Døskeland, S. O.; Herfindal, L. and Rongved, P. Bioorg. Med. Chem. 2017, 25 (7): 2285-2293. Paper II New prodrugs and analogues of the phenazine 5,10-dioxide natural products iodinin and myxin promote selective cytotoxicity towards human acute myeloid leukemia cells. Viktorsson, E. Ö.; Aesoy, R.; Støa, S.; Døskeland, S. O.; Herfindal, L. and Rongved, P. Prepared manuscript Paper III Synthesis, in vitro and in vivo biological evaluation of new oxysterols as modulators of the liver X receptors Åstrand, O. A. H.; Viktorsson, E. Ö.; Kristensen, A. L.; Ekeberg, D.; Røberg-Larsen, H.; Wilson, S. R.; Gabrielsen, M.; Sylte, I.; Rustan, A.; Thoresen, H.; Rongved, P.; Kase, E. T. J. Steroid. Biochem.. 2017, 165, 323-330. Paper IV Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations Viktorsson, E. Ö.; Gabrielsen, M.; Kumarachandran, N.; Sylte, I.; Rongved, P.; Åstrand, O. A. H.; Kase, E. Steroids 2017, 118, 119-127. VII Paper V Crystal structure of (S)-2-[(3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,- 8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-N- methoxy-N-methylpropanamide (Fernholz Weinreb amide) Viktorsson, E. Ö.; Åstrand, O. A. H.; Haseeb, R. S.; Görbitz, C. H. and Rongved, P. Acta. Crystallogr. E. 2015, 71 (3): 275-277 Patent application 1 Preparation of phenazine derivatives and cyclodextrin nanoparticle delivery thereof for treatment of cancer and infection. Døskeland, S. O.; Rongved, P.; Herfindal, L.; Le Borgne, M.; Viktorsson, E. Ö. and Åstrand, O. A. H. International publication number: WO 2015/063516 A2 2015.05.07.
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