Bilirubin: Jekyll and Hyde Pigment of Life

Transcription

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2 Progress in the Chemistry of Organic Natural Products 98 D.A. Lightner Bilirubin: Jekyll and Hyde Pigment of Life 123

3 Progress in the Chemistry of Organic Natural Products Founded by L. Zechmeister Editors: A.D. Kinghorn, Columbus, OH H. Falk, Linz J. Kobayashi, Sapporo Honorary Editor: W. Herz, Tallahassee, FL Editorial Board: V.M. Dirsch, Vienna S. Gibbons, London N.H. Oberlies, Greensboro, NC Y. Ye, Shanghai

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5 98 Progress in the Chemistry of Organic Natural Products Bilirubin: Jekyll and Hyde Pigment of Life; Pursuit of Its Structure Through Two World Wars to the New Millenium Author: David A. Lightner

6 Prof. A. Douglas Kinghorn, College of Pharmacy, Ohio State University, Columbus, OH, USA em. Univ.-Prof. Dr. H. Falk, Institut für Organische Chemie, Johannes-Kepler-Universität, Linz, Austria Prof. Dr. J. Kobayashi, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan ISSN ISSN (electronic) ISBN ISBN (ebook) DOI / Springer Wien Heidelberg New York Dordrecht London Library of Congress Control Number: Springer-Verlag Wien 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Cover picture: Crystals (left) of bilirubin-ixα (from CHCl 3 -CH 3 OH) photographed through polarized light. (Center) Crystalline bilirubin in bulk. (Right) Dilute solution of bilirubin in dimethyl sulfoxide. Image obtained by scanning on a flatbed scanner (Graphics courtesy of Prof. A.F. McDonagh, UCSF) Printed on acid-free paper Springer is part of Springer Science+Business Media (

7 This volume is dedicated to those who introduced me to bilirubin, Profs. Albert Moscowitz and Cecil J. Watson of the University of Minnesota, and to those who helped me become familiar with it, Prof. Med. Antony F. McDonagh of the University of California, San Francisco, and all of my students and postdoctoral fellows.

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9 Acknowledgments In the preparation of this work, special acknowledgment is due to the University of Nevada Library specialists Mr. Mark Lucas, who provided invaluable assistance in document retrieval, and Ms. Maggie Ressel, who made electronic search possible; to my Vienna- and Berlin-educated son, Dr. Derek Lightner, for helpful corrections and comments on reading the manuscript; likewise to em. Univ. Prof. Dr. Heinz Falk (Johannes Kepler Universität Linz, Austria) and Prof. Med. Antony F. McDonagh (University of California, San Francisco) for invaluable suggestions and careful editing; to o. Prof. Dr. Peter Laur (Rheinisch-Westfälische Technische Hochschule Aachen) and Prof. Falk for assistance in retrieving some biographical information; and to Stefano Abbate, a budding Latin scholar. Immense gratitude is due to Ms. Susan Grobman for technical assistance par excellence, for patiently preparing and expertly editing das Buch. vii

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11 Contents 1 Introduction Early Reviews, Current Objectives Background Early Scientific Investigations Advances in the 18th Century Color Diagnostics Emergence of a New Analytical Methodology: Quantitative Combustion Analysis Early 19th Century Pigment Separation from Bile and Gallstones Bilirubin and Biliverdin Separation from Bile by the Middle 19th Century Bile Pigments from Gallstones and Urine, and Their Combustion Analyses during the late 18th to mid-19th Centuries Bile Pigments from Gallstones in the Middle of the 19th Century Hämatoidin, Bilifulvin, and the Origin of Bile Pigments Bile Pigment Isolation, Purification, and Combustion Analysis in the 1860s and 1880s Georg Andreas Karl Städeler Gives the Name Bilirubin as a First Step Is Taken Toward Structure Identification Johann Ludwig Wilhelm (aka John Lewis William) Thudichum and Bilirubin Richard L. Maly and Bilirubin The Emergence of Bile Pigment Spectroscopy: Colorimetry and Its Applications Bilirubin Polemics of the 1870s ix

12 x Contents 2.12 Conjectural Chemistry and Bilirubin Polemics at the Close of the 19th Century Knowledge of Bilirubin Near the End of the 19th Century Advent of the Bilirubin Structure Proof Experimentally Derived Molecular Weight of Bilirubin at the End of the 19th Century Bilirubin Elemental Combustion Analyses and Molecular Weight Determinations at the Beginning of the 20th Century Molecular Fragmentation: Initial Approach to Bilirubin Structure Küster s Maleimides and Nencki s Hämopyrrol A Modern Proof of Bilirubin Structure Emerges Oskar Piloty and the Structure of Bilirubin Hans Fischer and the Early Structures of Bilirubin Fischer and Piloty Cleave Bilirubin in Half, The Piloty-Fischer Polemics Fischer s Bilirubinsäure, Xanthobilirubinsäure, and Bilirubin Structures ca The Alkylated Monopyrrole Components of Bilirubinsäure and Xanthobilirubinsäure The Monopyrrole Propionic Acid Components of Bilirubinsäure and Xanthobilirubinsäure Status and Conjectures Regarding Bilirubin and Hemin Structures circa Raison d être Behind Fischer s Failed Tetrapyrrole Structures Prior to Preparing the Way to the Constitutional Structure of Bilirubin Evolution of the Bilirubin Structure in the 1920s Tetrapyrrylethylene-Based Hemin and Bilirubin Kaput Küster-Fischer Polemics Schumm-Fischer Polemics Vindication of the Macrocyclic Porphyrin Structure The Structure of Bilirubin Reformulated The Status of Bilirubin in The Fischer Laboratory in the 1930s and the Structure of Bilirubin Serendipitous Discovery of New Dipyrrole Fragments of Mesobilirubin: Neobilirubinsäure and Neoxanthobilirubinsäure Synthetic Dipyrroles, Tetrapyrroles, Inhomogeneity, and Nefarious Mixture Melting Points

13 Contents xi A Major Breakthrough in Understanding the Structure of Bilirubin. Resolution of Discordant Melting Points and Synthesis of Mesobilirubin The Structure of Natural-Analytical Mesobilirubin Confirmed. Synthesis of Mesobilirubin-IXa Fischer Solves the Structure of Bilirubin Der Nitritkörper The Exo-vinyl Group of Bilirubin Bilirubin Structure Proof and Total Synthesis QED Hans Fischer, Finis Vitae Evolution of the Constitutional and Stereochemical Structure of Bilirubin Lactim or Lactam Tautomeric Structure? Configuration at the Exocyclic Double Bonds Proposing and Detecting Hydrogen Bonds Analysis of Bilirubin in Three Dimensions Chirality Considerations Bilirubin as a Chiral Molecule Bilirubin Conformational Dynamics by NMR Spectroscopy Conformational Dynamics by Molecular Mechanics Computation Bilirubin Chirality Revisited. Chiral Discrimination and Optical Activity Bilirubin Circular Dichroism from a First-Order Asymmetric Transformation Bilirubin as a Molecular Exciton. Absolute Configuration from Exciton Chirality Mapping Bilirubin Conformation to Exciton Chirality CD Stereocontrol of Bilirubin Conformational Enantiomerism by Intramolecular Buttressing Understanding and Translating Bilirubin Structure Bilirubin Chemistry Reawakened Thanks to Jaundice Phototherapy How Phototherapy Exposed Bilirubin (E)-Configuration Isomers (4Z,15E)- and (4E,15Z)-Bilirubin Diastereomers (Photobilirubin) Lumirubin and Isobilirubin Diastereomers (E)-Configuration Bilirubins from X-Ray Crystallography

14 xii Contents 9.3 The Glue that Binds. Persistence, Recognition, and Role of Hydrogen Bonds Understanding Dipyrrinone-Carboxylic Acid Hydrogen Bonding Misconceptions About Hydrogen Bonding Intramolecular Hydrogen Bonds and pk a. Un Cordon Sanitaire? Extrapolating from Bile Pigment Stereochemistry and Hydrogen Bonding to Synthetic Bilirubinoids Bilirubin. Quod Erat Faciendum Translations Translations to Section Translations to Section Translations to Section Translations to Section Translations to Section Translations to Section Translations to Section References Author Index Subject Index Listed in PubMed

15 Contributor David A. Lightner, Department of Chemistry, University of Nevada, Reno, NV, USA xiii