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Abstract of the Dissertation UNIVERSITY OF CALIFORNIA, SAN DIEGO Aminoglycoside Derivatives and Mimetics as RNA Binders A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry by Fang Zhao Committee in charge: Professor Yitzhak Tor, Chair Professor Jeffery D. Esko Professor Thomas Hermhann Professor Joseph M. O’Connor Professor Susan S. Taylor 2007 Copyrights© Fang Zhao, 2007 All rights reserved. The dissertation of Fang Zhao is approved, and it is acceptable in quality and form for publication on microfilm. Chair University of California, San Diego 2007 iii With love dedicated to Wenxiang Zhao and Zhiqin Wang, my parents. iv TABLE OF CONTENTS Signature Page .............................................................................................................. iii Dedication ..................................................................................................................... iv Table of Contents ............................................................................................................ v List of Symbols and Abbreviations.............................................................................. vii List of Figures ............................................................................................................... ix List of Tables .............................................................................................................. xiii Acknowledgement ...................................................................................................... xiv Curriculum Vitae .......................................................................................................... xv Abstract of the Dissertation ........................................................................................ xvi Chapter 1 ....................................................................................................................... 1 1.1 Introduction ........................................................................................................ 2 1.2 RNA as a Drug Target ....................................................................................... 7 1.3 Aminoglycosides ............................................................................................. 12 1.4 Design of RNA Binders ................................................................................... 22 1.5 Goals ................................................................................................................ 30 References ............................................................................................................... 31 Chapter 2 ..................................................................................................................... 37 2.1 Introduction ...................................................................................................... 38 2.2 Design of Conformationally Restricted Aminoglycosides .............................. 41 2.3 Synthesis .......................................................................................................... 46 v 2.4 Spectroscopic Characterizations. ..................................................................... 50 2.5 15N NMR Studies and pKa measurement ........................................................ 54 2.6 Ligand Binding to the A– Site RNA ................................................................ 57 2.7 Crystal Structure .............................................................................................. 60 2.8 Discussion ........................................................................................................ 66 References ............................................................................................................... 69 Chapter 3 ..................................................................................................................... 73 3.1 Introduction ...................................................................................................... 74 3.2 Synthesis of the 4, 5 substituted amino–cyclohexanecarboxylic acids ........... 78 3.3 Conformation Analysis for Cyclohexyl Oxiranes ........................................... 91 References ............................................................................................................... 98 Chapter 4 ................................................................................................................... 100 4.1 Synthetic Experimental Section ...................................................................... 101 4.1.1 Materials .................................................................................................. 101 4.1.2 NMR Instrumentation .............................................................................. 101 4.1.3 Synthesis of conformationally-constrained Neomycin B (2a) ................ 101 4.1.4 Synthesis of conformationally-constrained Neomycin B (2b) ................ 112 4.1.5 Synthesis of 2-aminocyclohexancarboxylic acids. ............................ 118 References ............................................................................................................. 127 vi LIST OF SYMBOLS AND ABBREVIATIONS Å angstrom chemical shift difference o degree atm. atmosphere ave. average Boc tert-butyloxycarbonyl br broad Bu butyl Bz benzyl calcd calculated DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide equiv. equivalent ESI MS electrospray ionization mass spectrum Et ethyl FAB MS fast atom bombardment mass spectrum HPLC high performance liquid chromatography HR-MS high resolution mass spectrometry iPr iso-propyl vii K kelvin kcal kilo-calorie L liter M mol L-1 Me methyl mg mili-gram mL mili-liter mmol mili-mole mol mole NMR nuclear magnetic resonance Ph phenyl s second t-Bu tertial-butyl TEA triethylamine tert tertial Tf triflate THF tetrahydrofuran TLC thin layer chromatography UV ultraviolet Vis visible viii LIST OF FIGURES Figure 1.1 The central dogma of biology..................................................................... 2 Figure 1.2 Schematic view of protein synthesis. ......................................................... 3 Figure 1.3 Steps at which RNAs have been found to modulate gene expression. ....... 4 Figure 1.4 a) RNA secondary structure feature. b) Tertiary structure of tRNA. ........ 9 Figure 1.5 Representative RNA–binding small molecules. ....................................... 11 Figure 1.6 Representative aminoglycoside antibiotics .............................................. 14 Figure 1.7 The ribosomal 16S RNA sequence and the aminoglycoside binding sites. ............................................................................................................................. 15 Figure 1.8 Structure of natural and synthetic deoxy–tobramycin derivatives. .......... 18 Figure 1.9 Modeling shows the structurally electrostatic complementarity between hammerhead RNA and neomycin B. .................................................................. 20 Figure 1.10 Structure of Acridine–Neomycin conjugates. ........................................ 23 Figure 1.11 Structure of aminoglycosides and guanidinoglycosides......................... 24 Figure 1.12 Structure of Pt–aminoglycoside conjugates. .......................................... 25 Figure 1.13 Structure of tobramycin and pyranmycin analogs. ................................. 26 Figure 1.14 Structure of neamine derivative for targeting oncogenic RNA .............. 28 Figure 1.15 a) Representative designed piperidine glycoside ligand. b) Three– dimensional model of the designed piperidine glycoside superimposed on paromamine, showing their conformational similarity. c) Model of the piperidine glycoside 1 docked in the three–dimensional structure of the bacterial decoding– site RNA in complex with paromomycin. .......................................................... 29 Figure 2.1 a) Chemical structures of the neomycin class aminoglycosides studied. b) The conformation of paromomycin bound to A– site11, neomycin bound to the TAR8, a SELEX– derived aptamer9 and the Tau exon.10 ................................... 40 Figure 2.2 Conformationally constrained neomycin (2a) and paromomycin (2b). ... 43 Figure 2.3 Torsional angles of aminoglycosides free in solution or bound to A– site or the TAR RNAs. ............................................................................................ 44 Figure 2.4 Synthesis of Conformationally Constrained Analogues 2a. ..................... 47 ix Figure 2.5 Synthesis of Conformationally Constrained Analogues 2a. ..................... 48 Figure 2.6 1H NMR (top) and 1H– 13C gHSQC (bottom) spectrums of restricted neomycin 2a ........................................................................................................ 52 Figure 2.7 1H– 13C gHMBC spectrum of restricted neomycin B 2a (left) and an expansion (right) highlighting the cross– peak from 5''–Hb to 2'–C. .................. 53 Figure 2.8 15N NMR spectra of restricted neomycin 2a and neomycin 1a at pH 10.7 ............................................................................................................................. 54 Figure 2.9 a) RNA construct A– site 2AP (1492) containing the ribosomal decoding site used in this study. b) The structure of fluorescent nucleoside 2– aminopurine (2AP) that is incorporated at position 1492. c) Sample binding isotherms of paromomycin (1b) and restricted paromomycin (2b) binding to
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