DOCSLIB.ORG

Synthesis and Characterization of C8 Analogs of C-Di-Gmp;

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Synthesis and Characterization of C8 Analogs of C-Di-Gmp; SYNTHESIS AND CHARACTERIZATION OF C8 ANALOGS OF C-DI-GMP; NEW SYNTHETIC METHOD FOR 5’-CAPPED OLIGORIBONUCLEOTIDES by ELIZABETH VELIATH A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Program in Chemistry written under the direction of Roger A. Jones and approved by ________________________ ________________________ ________________________ ________________________ New Brunswick, New Jersey January, 2011 ABSTRACT OF THE DISSERTATION Synthesis and Characterization of C8 Analogs of c-di-GMP; New Synthetic Method for 5’-Capped Oligoribonucleotides By ELIZABETH VELIATH Dissertation Director: Roger A. Jones This research is centered on two projects of biological importance composed of RNA –based compounds: C8 analogs of cyclic diguanosine monophosphate (c-di-GMP) and 5’-capped oligoribonucleotides. c-di-GMP is an important bacterial second messenger molecule that is critical for the transition between a biofilm-protected sessile state and a virulent, single cellular motile state in species like V. Cholerae and S.Typhimurium. The synthesis and solution phase structural analysis of a family of C8-modified analogs is described. Starting from unmodified c-di-GMP, elaboration at the C8 position of both guanine moieties of c-di- GMP resulted in the bromo, thio, methylthio, phenyl, and meta-acetylphenyl analogs. Biophysical studies of all five compounds was performed using 1D and (1H, 31P, 13C) and 2D (DOSY, HMBC/HMQC) NMR to ascertain the level of G-quadruplex formation. It was found that only c-di-Br-GMP as the K+ salt form adopts the formation of higher order complexes containing guanine quartet structures. All analogs have an NMR-visible amino resonance that is most prominent at low temperatures due to protection from exchange by the self-stacking, and that disappears at elevated ii temperatures, which does not occur in with the 8-bromo-GMP monomer illustrating the special structural characteristics of the symmetric dimer. Capped RNA has a unique 5’-end structure containing a terminal N7-methylated guanosine that is joined via a triphosphate bridge to the 5’-OH of all eukaryotic mRNAs. This structure plays a vital role in regulating RNA maturation, processing, transport and translation, but capped RNA is extremely difficult to synthesize chemically due to its instability. A new protection strategy was devised that uses a lipophilic dimethoxytrityl (DMT) group on the amino group of the N7-methylated guanine activated capping reagent. This allows efficient purification of the final capped RNA on reverse-phase HPLC. Additionally, the DMT group increases the capping reagent solubility in organic solvents which improves the final coupling step. The synthetic method is general to include a variety of mixed sequence oligonucleotides, and is compatible with reverse-phase HPLC. This method has been used to synthesize and purify the unmodified cap structure m7GpppG, the individual 7 7 diastereomers of the α-thiophosphate analog m Gppp(s)G, m GpppT8 and mixed 7 7 7 sequences of m Gppp-(2’-O-Me-GAUGC), m Gppp-(2’-O-Me-GAUGC)2, m Gppp-(2’- 7 O-Me-GUAUC)4 and m Gppp-(GUAUC)4. iii DEDICATION This work is dedicated to my husband Aaron, whose continued support, encouragment and understanding, has been absolutely invaluable to me throughout my graduate career; to my brother, Andrew, for his friendship and generosity; and to my parents, George Veliath and Ginger Cyr, for always believing in me. I also wish to extend my deepest thanks to my extended family and friends for their encouragement and support as well. iv ACKNOWLEDGEMENTS I am extremely grateful to my advisor, Professor Roger A. Jones, for his guidance, inspiration and continuous support, throughout my graduate research in the field of nucleic acid chemistry. I thank him for the countless conversations that have helped hone my skills in becoming a better scientist. I am extremely grateful to Professor Barbara L. Gaffney for many useful conversations pertaining to chemistry, for her daily role as a mentor and for her friendship and encouragment. I would like to thank the members of my thesis committee, Professor Jeehiun K. Lee, Professor Lawrence Williams from the Department of Chemistry at Rutgers and Professor Ed LaVoie from the Department of Pharmacy at Rutgers for their advice, time and helpful suggestions. I would like to thank Professor Kenneth Breslauer for help with spectrophotometric instrumentation; and Dr. Jens Volker for many useful conversations pertaining to spectroscopy of oligonucleotides. I would like to thank the past Jones group lab members, as well as the friends I have forged strong friendships with over the years at Rutgers, for making my graduate study a very enriching experience. v I am grateful for the significant financial support provided by the Rutgers Excellence Fellowship, the GAANN Fellowship, NIH and the Department of Chemistry and Chemical Biology at Rutgers, the State University of New Jersey. vi TABLE OF CONTENTS Abstract ..……………………………………………………………………………. ii Dedication ………………………………………………………………………….. iv Acknowledgements ………………………………………………………………….. v Table of Contents ………………………………………………………………….. viii List of Figures ………………………………………………………………………. xii List of Schemes ……………………………………………………………………. xiv List of Tables ……………………………………………………………………….. xvii List of Abbreviations …………………………………………………………...…. xviii Chapter 1 A Brief Overview of Synthetic Ribonucleoside Chemistry ………………………....1 References …………………………………………………………………………. 2 Chapter 2 Synthesis and Characterization of C8 Analogs of c-di-GMP ………………………3 1. Biological Background of c-di-GMP ………………………………………….. 3 1.1 c-di-GMP as Bacterial Second Messenger Signaling Molecule ………….. 3 1.2 Discovery of c-di-GMP …………………………………………………... 4 1.3 c-di-GMP Regulates Biofilm Production ………………………………… 4 1.4 c-di-GMP Regulates Virulence and Pathogenesis …………………………6 1.5 Enzymes that Synthesize and Degrade c-di-GMP …………………………8 1.6 c-di-GMP Target Receptors ………………………………………………..8 1.7 Temporal and Spatial Regulation of c-di-GMP Levels …………………...12 1.8 Effects of c-di-GMP on Mammalian Cells ………………………………. 14 vii 1.9 References ………………………………………………………………..15 2. Synthetic Background of c-di-GMP and Analogs ……………………………18 2.1 c-di-GMP Synthetic Introduction ………………………………………..18 2.2 Phosphotriester Chemistry ……………………………………………….19 2.3 H-Phosphonate Chemistry ……………………………………………….21 2.4 Combination of Phosphotriester, H-Phosphonate, and Phosphoramidite Chemistry ………………………………………………………………...23 2.5 Other Methods ……………………………………………………………28 2.6 References ………………………………………………………………..29 3. Synthesis of C8 Analogs of c-di-GMP …………………………….………….31 3.1 Introduction ……………………………………………………………....31 3.2 Synthesis of c-di-Br-GMP ………………………………………………..31 3.3 Synthesis of c-di-thio-GMP ………………………………………………34 3.4 Synthesis of c-di-methylthio-GMP ……………………………………….38 3.5 Synthesis of c-di-phenyl-GMP and c-di-acetylphenyl-GMP …….……….39 3.6 Conclusions ……………………………………………………….………45 3.7 Experimental Procedures …………………………………………………46 3.8 References ……………………………………………………….………..52 3.9 Appendix …………………………………………………………………54 4. Biophysical Studies of C8 Analogs of c-di-GMP …………………………….78 4.1 Introduction ………………………………………………………………78 4.2 Previous Work on the Biophysical Studies of c-di-GMP ………………..78 4.3 Biophysical Studies of c-di-Br-GMP Salt Forms ………………………..81 viii 4.3.1 NMR Studies of c-di-Br-GMP ………………………………..81 4.3.1.1 Introduction …………………………………………...81 4.3.1.2 K+ form of c-di-Br-GMP ……………………………...82 4.3.1.3 Na+ form of c-di-Br-GMP …………………………….86 4.3.1.4 Li+ form of c-di-Br-GMP ……………………………..90 4.3.1.5 TEA+ form of c-di-Br-GMP ……………………….….91 4.3.1.6 Salt Forms of 8-Br-GMP Monomer ……………….….93 4.3.1.7 Conclusions for NMR Studies of c-di-Br-GMP ….…..96 4.3.2 UV Studies of c-di-Br-GMP ……………………………….…96 4.3.2.1 UV Melting Study for K+ and Na+ Forms of c-di-Br-GMP ………………………………………….96 4.3.2.2 Results ………………………………………………..97 4.3.3 Further Investigation of NMR-Visible N2-Amino Resonance .98 4.3.3.1 Heteronuclear 2D NMR of K+ and Na+ Forms of c-di-Br-GMP …………………………………………99 4.3.3.2 Effect of pH on UV Profile of Na+ Form of c-di-Br-GMP ………………………………….……..101 4.4 Biophysical Studies of c-di-thio-GMP: K+, Na+, and TEA+ forms …..102 4.5 Biophysical Studies of c-di-methylthio-GMP: K+, Na+, and TEA+ forms ………………………………………………………105 4.6 Biophysical Studies of c-di-phenyl-GMP: K+, Na+, and TEA+ forms ..107 4.7 Biophysical Studies of c-di-acetylphenyl-GMP: K+ and Na+ forms ….110 4.8 NMR Re-examination of c-IMP-GMP: K+ form ……………………..112 ix 4.9 Conclusions ……………………………………………………………114 4.10 References ……………………………………………………………..116 Chapter 3 New Synthetic Method for 5’-Capped Oligoribonucleotides ……………………..118 1. Capped RNA Biological Background …………………………………………….118 1.1 Introduction ……………………………………………………………...118 1.2 Biological Function of Capped RNA ……………………………………118 1.3 Chemical Structure of Capped RNA …………………………………….119 1.4 Role of Capped RNA in Regulating RNA Decay ……………………….122 1.4.1 Deadenylation-Independent Decay Mechanisms ………………122 1.4.2 Deadenylation-Dependant Decay Mechanisms ………………..124 1.5 References ………………………………………………………………..126 2. Synthetic Background of Capped RNA ……………………………….………….129 2.1 Introduction ………………………………………………….…………..129 2.2 Enzymatic Methods ……………………………………………………..129 2.3 Combination of Enzymatic and Chemical Methods …………………….130 2.4 Chemical Methods ………………………………………………………132 2.5 References ……………………………………………………………….145 3. Synthesis of 5’-Capped Oligoribonucleotides
Load more

Recommended publications
  • Approach to Site-Selective Protein Modification JUSTIN M
    A “Tag-and-Modify” Approach to Site-Selective Protein Modification JUSTIN M. CHALKER, GONC-ALO J. L. BERNARDES, AND BENJAMIN G. DAVIS* Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom RECEIVED ON FEBRUARY 27, 2011 CONSPECTUS ovalent modification can expand a protein's functional capacity. Fluorescent or radioactive labeling, for instance, allows C imaging of a protein in real time. Labeling with an affinity probe enables isolation of target proteins and other interacting molecules. At the other end of this functional spectrum, protein structures can be naturally altered by enzymatic action. ProteinÀprotein interactions, genetic regulation, and a range of cellular processes are under the purview of these post- translational modifications. The ability of protein chemists to install these covalent additions selectively has been critical for elucidating their roles in biology. Frequently the transformations must be applied in a site-specific manner, which demands the most selective chemistry. In this Account, we discuss the development and application of such chemistry in our laboratory. A centerpiece of our strategy is a “tag-and-modify” approach, which entails sequential installation of a uniquely reactive chemical group into the protein (the “tag”) and the selective or specific modification of this group. The chemical tag can be a natural or unnatural amino acid residue. Of the natural residues, cysteine is the most widely used as a tag. Early work in our program focused on selective disulfide formation in the synthesis of glycoproteins. For certain applications, the susceptibility of disulfides to reduction was a limitation and prompted the development of several methods for the synthesis of more stable thioether modifications.
    [Show full text]
  • Ncomms12703.Pdf
    ARTICLE Received 17 Feb 2016 | Accepted 26 Jul 2016 | Published 2 Sep 2016 DOI: 10.1038/ncomms12703 OPEN Chemoselective synthesis and analysis of naturally occurring phosphorylated cysteine peptides Jordi Bertran-Vicente1, Martin Penkert1,2, Olaia Nieto-Garcia1,2, Jean-Marc Jeckelmann3, Peter Schmieder1, Eberhard Krause1 & Christian P. R. Hackenberger1,2 In contrast to protein O-phosphorylation, studying the function of the less frequent N- and S-phosphorylation events have lagged behind because they have chemical features that prevent their manipulation through standard synthetic and analytical methods. Here we report on the development of a chemoselective synthetic method to phosphorylate Cys side-chains in unprotected peptides. This approach makes use of a reaction between nucleophilic phosphites and electrophilic disulfides accessible by standard methods. We achieve the stereochemically defined phosphorylation of a Cys residue and verify the modification using electron-transfer higher-energy dissociation (EThcD) mass spectrometry. To demonstrate the use of the approach in resolving biological questions, we identify an endogenous Cys phosphorylation site in IICBGlc, which is known to be involved in the carbohydrate uptake from the bacterial phosphotransferase system (PTS). This new chemical and analytical approach finally allows further investigating the functions and significance of Cys phosphorylation in a wide range of crucial cellular processes. 1 Leibniz-Institut fu¨r Molekulare Pharmakologie (FMP), Robert-Ro¨ssle-Str. 10, D-13125 Berlin, Germany. 2 Humboldt-Universita¨t zu Berlin, Institut fu¨r Chemie, Brook-Taylor-Str. 2, D-12489 Berlin, Germany. 3 Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland. Correspondence and requests for materials should be addressed to C.P.R.H.
    [Show full text]
  • Organophosphate Insecticides
    CHAPTER 4 HIGHLIGHTS Organophosphate Insecticides Acts through phosphorylation of the acetylcholinesterase enzyme Since the removal of organochlorine insecticides from use, organophosphate at nerve endings insecticides have become the most widely used insecticides available today. More Absorbed by inhalation, than forty of them are currently registered for use and all run the risk of acute ingestion, and skin and subacute toxicity. Organophosphates are used in agriculture, in the home, penetration in gardens, and in veterinary practice. All apparently share a common mecha- Muscarinic, nicotinic & CNS nism of cholinesterase inhibition and can cause similar symptoms. Because they effects share this mechanism, exposure to the same organophosphate by multiple routes or to multiple organophosphates by multiple routes can lead to serious additive Signs and Symptoms: toxicity. It is important to understand, however, that there is a wide range of Headache, hypersecretion, toxicity in these agents and wide variation in cutaneous absorption, making muscle twitching, nausea, specific identification and management quite important. diarrhea Respiratory depression, seizures, loss of consciousness Toxicology Miosis is often a helpful Organophosphates poison insects and mammals primarily by phosphory- diagnostic sign lation of the acetylcholinesterase enzyme (AChE) at nerve endings. The result is a loss of available AChE so that the effector organ becomes overstimulated by Treatment: the excess acetylcholine (ACh, the impulse-transmitting substance) in the nerve Clear airway, improve tissue ending. The enzyme is critical to normal control of nerve impulse transmission oxygenation from nerve fibers to smooth and skeletal muscle cells, glandular cells, and Administer atropine sulfate autonomic ganglia, as well as within the central nervous system (CNS).
    [Show full text]
  • Asymmetric Synthesis of Organophosphates and Their
    ASYMMETRIC SYNTHESIS OF ORGANOPHOSPHATES AND THEIR DERIVATIVES Thesis Submitted to The College of Arts and Sciences of the UNIVERSITY OF DAYTON In Partial Fulfillment of the Requirements for The Degree of Master of Science in Chemistry By Batool J. Murtadha Dayton, Ohio May 2020 ASYMMETRIC SYNTHESIS OF ORGANOPHOSPHATES AND THEIR DERIVATIVES Name: Murtadha, Batool J. APPROVED BY: __________________________________ Jeremy Erb, Ph.D. Research Advisor Assistant Professor Department of Chemistry University of Dayton ___________________________________ Vladimir Benin, Ph.D. Professor of Chemistry Department of Chemistry University of Dayton ___________________________________ Justin C. Biffinger, Ph.D. Committee Member Assistant Professor Department of Chemistry University of Dayton ii © Copyright by Batool J. Murtadha All rights reserved 2020 iii ABSTRACT ASYMMETRIC SYNTHESIS OF ORGANOPHOSPHATES AND THEIR DERIVATIVES Name: Murtadha, Batool J. University of Dayton Advisor: Dr. Jeremy Erb Organophosphorus compounds (OPs) are widely used in the agricultural industry especially in the pesticide market. Phosphates play a huge role as biological compounds in the form of energy carrier compounds like ATP, and medicine as antivirals. OPs have become increasingly important as evidenced by the publication of new methods devoted to their uses and synthesis. These well-established studies lay the basis for industrial organic derivatives of phosphorus preparations. The current work explored methods of synthesizing chiral organophosphate triesters. We experimented with different processes roughly divided into either an electrophilic or nucleophilic strategy using chiral Lewis acids, organocatalysts (HyperBTM), activating agents, and chiral auxiliaries with the goal of control stereoselectivity. These methods were explored through the use of different starting materials like POCl3, triethyl phosphate, methyl phosphordichloradate, and PSCl3.
    [Show full text]
  • Environmental Health Criteria 63 ORGANOPHOSPHORUS
    Environmental Health Criteria 63 ORGANOPHOSPHORUS INSECTICIDES: A GENERAL INTRODUCTION Please note that the layout and pagination of this web version are not identical with the printed version. Organophophorus insecticides: a general introduction (EHC 63, 1986) INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 63 ORGANOPHOSPHORUS INSECTICIDES: A GENERAL INTRODUCTION This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization. Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization World Health Orgnization Geneva, 1986 The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination
    [Show full text]
  • Biosensors for Detection of Organophosphate Exposure by New Diethyl Thiophosphate-Specifc Aptamer
    Biosensors for Detection of Organophosphate Exposure by New Diethyl Thiophosphate-Specic Aptamer Napachanok Mongkoldhumrongkul Swainson Kasetsart University - Bangkhen Campus: Kasetsart University Chonnikarn Saikaew Kasetsart University - Bangkhen Campus: Kasetsart University Kanyanat Theeraraksakul Kasetsart University - Bangkhen Campus: Kasetsart University Pongsakorn Aiemderm Kasetsart University - Bangkhen Campus: Kasetsart University Rimdusit Pakjira Department of Disease Control Charoenkwan Kraiya Chula: Chulalongkorn University Sasimanas Unajak Kasetsart University - Bangkhen Campus: Kasetsart University kiattawee choowongkomon ( [email protected] ) Kasetsart University https://orcid.org/0000-0002-2421-7859 Research Article Keywords: Aptasensor, organophosphate metabolites, diethyl thiophosphate, electrochemical impedance spectroscopy, capillary electrophoresis Posted Date: February 23rd, 2021 DOI: https://doi.org/10.21203/rs.3.rs-217995/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published at Biotechnology Letters on July 6th, 2021. See the published version at https://doi.org/10.1007/s10529-021-03158-2. Page 1/17 Abstract Objective An aptamer specically binding to diethyl thiophosphate (DETP) was constructed and incorporated in an optical sensor and electrochemical impedance spectroscopy (EIS) to enable the specic measurement of DETP as a metabolite and a biomarker of exposure to organophosphates. Results DETP-bound aptamer was selected from the library using capillary electrophoresis-systematic evolution of ligands by exponential enrichment (CE-SELEX). A colorimetric method revealed the aptamer had the highest anity to DETP with a mean Kd value (± SD) of 0.103 ± 0.014 µM. Changes in resistance using EIS showed selectivity of the aptamer for DETP higher than for dithiophosphate (DEDTP) and diethyl phosphate (DEP) which have similar structure and are metabolites of some of the same organophosphates.
    [Show full text]
  • NMR Studies of Phosphorus Ligand Complexes of Silver and Cobalt Steven Mark Socol Iowa State University
    Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1983 NMR studies of phosphorus ligand complexes of silver and cobalt Steven Mark Socol Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Inorganic Chemistry Commons Recommended Citation Socol, Steven Mark, "NMR studies of phosphorus ligand complexes of silver and cobalt " (1983). Retrospective Theses and Dissertations. 8962. https://lib.dr.iastate.edu/rtd/8962 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS This reproduction was made from a copy of a document sent to us for microfilming. While the most advanced technology has been used to photograph and reproduce this document, the quality of the reproduction is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help clarify markings or notations which may appear on this reproduction. 1.The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting through an image and duplicating adjacent pages to assure complete continuity. 2. When an image on the film is obliterated with a round black mark, it is an indication of either blurred copy because of movement during exposure, duplicate copy, or copyrighted materials that should not have been filmed.
    [Show full text]
  • Synthesis and Characterization of Seven Thiophosphate
    SYNTHESIS AND CHARACTERIZATION OF SEVEN THIOPHOSPHATE ANALOGS OF CYCLIC DIGUANOSINE MONOPHOSPHATE by JIANWEI ZHAO A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Program in Chemistry and Chemical Biology written under the direction of Professor Roger A. Jones and approved by ________________________ ________________________ ________________________ ________________________ New Brunswick, New Jersey [May, 2009] ABSTRACT OF THE DISSERTATION SYNTHESIS AND CHARACTERIZATION OF SEVEN THIOPHOSPHATE ANALOGS OF CYCLIC DIGUANOSINE MONOPHOSPHATE by JIANWEI ZHAO Dissertation Director: Professor Roger A. Jones Cyclic diguanosine monophosphate (c-di-GMP) was first identified as an activator of bacterial cellulose synthase in 1987. Since then, it has been recognized as an important second messenger molecule in many bacterial processes, including cellulose synthesis, biofilm formation, and host-pathogen interactions. More recently, it found to stimulate innate immunity in mammals. The monothiophosphate analog was synthesized some years ago and was shown to be a highly potent activator/second messenger with a high stability to enzymatic degradation. In the work presented here, synthetic methods have been developed to synthesize mono-, di- and trithiophosphate c-di-GMP analogs. All seven diastereomers of these analogs have been separated and purified. Stereochemistry of the two diastereomers of ii the monothioate analog was assigned by enzymatic digestion of the linear dimer, as well as direct enzymatic degradation of the cyclic dimers. In addition, the same linear dimer was cyclized to produce a cyclic dimer of known configuration. The correlation between stereochemistry and 31P NMR chemical shifts of the two diastereomers of the monothioate was then used to assign configurations of the di- and trithiophosphate analogs.
    [Show full text]
  • Cyclophostin, (±)-Cyclipostin P, Their Phosphonate Analogs and New
    University of Missouri, St. Louis IRL @ UMSL Dissertations UMSL Graduate Works 8-2-2011 Synthesis of (±)-Cyclophostin, (±)-Cyclipostin P, Their hoP sphonate Analogs and New Chemistry of Vinyl Phosphonates Raj Kumar Malla University of Missouri-St. Louis, [email protected] Follow this and additional works at: https://irl.umsl.edu/dissertation Part of the Chemistry Commons Recommended Citation Malla, Raj Kumar, "Synthesis of (±)-Cyclophostin, (±)-Cyclipostin P, Their hospP honate Analogs and New Chemistry of Vinyl Phosphonates" (2011). Dissertations. 416. https://irl.umsl.edu/dissertation/416 This Dissertation is brought to you for free and open access by the UMSL Graduate Works at IRL @ UMSL. It has been accepted for inclusion in Dissertations by an authorized administrator of IRL @ UMSL. For more information, please contact [email protected]. Synthesis of (±)-Cyclophostin, (±)-Cyclipostin P, Their Phosphonate Analogs and New Chemistry of Vinyl Phosphonates by Raj Kumar Malla A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) University of Missouri-St. Louis August, 2011 Committee Prof. Christopher D. Spilling (Chair and Advisor) Prof. Alexei V. Demchenko Prof. Cynthia M. Dupureur Prof. Eike B. Bauer Abstract Synthesis of (±)-Cyclophostin, (±)-Cyclipostin P, Their Phosphonate Analogs and New Chemistry of Vinyl Phosphonates Raj Kumar Malla Doctor of Philosophy University of Missouri-St. Louis Prof. Christopher D. Spilling, Advisor This work is divided into 2 parts: a) total synthesis of (±)-cyclophostin, (±)-cyclipostin P and their monocyclic analogs b) development of a metathesis based methodology for transformation of vinyl phosphonates. Cyclophostin (1) and cyclipostins (2) are bioactive natural bicyclic organophosphates.
    [Show full text]
  • Page 1 of 37 Pleasepolymer Do Not Chemistryadjust Margins
    Polymer Chemistry Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/polymers Page 1 of 37 PleasePolymer do not Chemistryadjust margins Polymer Chemistry Review Phosphorylation of bio-based compounds: state of the art Nicolas Illy,a,b,* Maxence Fache,c Raphaël Ménard,c Claire Negrell,c Sylvain Caillol,c and Ghislain Received 00th January 20xx, Davidc Accepted 00th January 20xx Over the last few years more and more papers have been devoted to phosphorus-containing DOI: 10.1039/x0xx00000x polymers, mainly due to their fire resistance, excellent chelating and metal-adhesion properties. www.rsc.org/ Nevertheless, sustainability, reduction of environmental impacts and green chemistry are increasingly guiding the development of the next generation of materials.
    [Show full text]
  • Studies of Properties of Derivatives of 1-Phospha-5-Aza-2,6,9-Trioxabicyclo[3.3.3]
    Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1983 Studies of properties of derivatives of 1-phospha-5-aza-2,6,9-trioxabicyclo[3.3.3]undecane and structurally related molecules Leslie Earl Carpenter II Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Inorganic Chemistry Commons Recommended Citation Carpenter, Leslie Earl II, "Studies of properties of derivatives of 1-phospha-5-aza-2,6,9-trioxabicyclo[3.3.3]undecane and structurally related molecules " (1983). Retrospective Theses and Dissertations. 8457. https://lib.dr.iastate.edu/rtd/8457 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS This reproduction was made from a copy of a document sent to us for microfilming. While the most advanced technology has been used to photograph and reproduce this document, the quality of the reproduction is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help clarify markings or notations which may appear on this reproduction. 1. The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages.
    [Show full text]
  • Synthesis and Evaluation of Phosphoramidate and Phosphorothioamidate Ana‐ Logues of Amiprophos Methyl As Potential Antimalarial Agents
    Accepted Manuscript Synthesis and evaluation of phosphoramidate and phosphorothioamidate ana‐ logues of amiprophos methyl as potential antimalarial agents Christine Mara, Enda Dempsey, Angus Bell, James W. Barlow PII: S0960-894X(11)01034-1 DOI: 10.1016/j.bmcl.2011.07.088 Reference: BMCL 17857 To appear in: Bioorganic & Medicinal Chemistry Letters Received Date: 16 March 2011 Revised Date: 22 July 2011 Accepted Date: 23 July 2011 Please cite this article as: Mara, C., Dempsey, E., Bell, A., Barlow, J.W., Synthesis and evaluation of phosphoramidate and phosphorothioamidate analogues of amiprophos methyl as potential antimalarial agents, Bioorganic & Medicinal Chemistry Letters (2011), doi: 10.1016/j.bmcl.2011.07.088 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Synthesis and evaluation of phosphoramidate and phosphorothioamidate analogues of amiprophos methyl as potential antimalarial agents Christine Maraa, Enda Dempseyb, Angus Bellb & James W. Barlowa* aDepartment of Pharmaceutical & Medicinal Chemistry, Royal College of Surgeons in Ireland, Stephens Green, Dublin 2, Ireland. Tel. +353 1 402 8520. Fax +353 1 402 2765. bDept. of Microbiology, School of Genetics & Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin 2, Ireland. Email address: [email protected] (J. W. Barlow) *corresponding author INSERT GRAPHICAL ABSTRACT HERE A series of phosphoramidate and phosphorothioamidate compounds based on the lead antitubulin herbicidal agents amiprophos methyl (APM) and butamifos were synthesised and evaluated for antimalarial activity.
    [Show full text]