The role of phosphonates in living systems

214 Pages·1983·12.24 MB·English

by  Hilderbrand

The Role
of
Phosphonates
in
Living Systems
Editor
Richard L. Hilderbrand,� Ph• D• 9L CDR
Biochemist
Naval Biosciences Laboratory
Oakland, California
CRC Press
Taylor & Francis Group
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Library of Congress Cataloging in Publication Data
Main entry under title:
The Role of phosphonates in living systems.
Bibliography: p.
Includes index.
1. Phosphonic acids—Physiological effect.
2. Phosphonic acids—Metabolism. 3. Phosphonates—
Physiological effect. 4. Phosphonates—Metabolism.
I. Hilderbrand, Richard L., 1946-
QP801.P56R64 1983� 574.19’214� 82-14708
ISBN 0-8493-5724-1
A Library of Congress record exists under LC control number: 82014708
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PREFACE
Phosphorus is required for growth, health, and reproduction in all forms of plants and
animals. Since derivatives of orthophosphate occur naturally and occupy such important
roles in life processes, it is apparent that an understanding of these roles might allow outside
manipulation to facilitate, as in the therapeutic use of drugs, or to interfere with, as in the
use of pesticides, normal life processes. Because of the unique character of the carbon-
phosphorus bond and its effect on the phosphorus moiety, the phosphonates are of increasing
importance to the facilitation of, or interference with, normal life processes, and to industrial
processes using phosphate derivatives. Although all organic esters of phosphate are loosely
classified as organophosphates, it is the phosphonate class of organophosphates, which
contain a carbon-phosphorus covalent bond, that consists of "true" organophosphates.
Throughout the last three decades, a large amount of information on phosphonates has
accumulated, but has not been compiled. At this time of the increasing importance of the
phosphonate class of molecules, this information needs to be drawn together to make a
manageable volume for use as a reference text and as a learning text for interested persons.
In compiling a volume of the size planned, discussion must be held to a minimum on the
peripheral aspects of phosphonates. Thus, some information has not received the discussion
that it may well deserve. For the unintentional oversight of significant ideas, I assume full
responsibility. It is desirable that in the future there be more thorough discussion of all
aspects of the subject.
The U.S. Navy (the Naval Medical Research and Development Command and the Naval
Medical Research Institute) has been supportive in this effort and I acknowledge that with
gratitude. Despite that support, however, the opinions and assertions contained herein are
the private views of the authors and are not to be construed as either official statements or
as reflecting the views of the U.S. Navy.
I would like to thank CRC Press, Inc. for publishing this manuscript, the individual
authors for their cooperation and contributions, Mrs. P. J. Gergely for her superb typing,
and Mrs. Gale E. Crain for her editorial assistance. Then there are those, to whom my debt
is more long-standing but no less real, who have been mentors over the years. My thanks
to Dr. Thomas 0. Henderson and Dr. Terrill C. Myers of the University of Illinois, Medical
Center Campus, for introducing me to scientific research and, specifically, to studies of the
role phosphonates play in living systems. Lastly, I dedicate this work to Heidi and Tim,
my two children.
Richard L. Hilderbrand, Ph.D.
1982
THE EDITOR
Richard L. Hilderbrand, Ph.D., is currently a biochemist at the Naval Biosciences
Laboratory, Oakland, Calif. In 1968, he graduated from Southwest Baptist College, Boliver,
Mo. with a major in biology and a minor in chemistry. His graduate work was in biological
chemistry and was completed in 1972 at the Graduate School, University of Illinois, Medical
Center Campus, Chicago. Immediately upon receiving his degree, Dr. Hilderbrand entered
active duty with the U.S. Navy and is currently a Lieutenant Commander in the Medical
Service Corps. Previously, he has been assigned duty at the Naval Medical Research Unit
#1, Berkeley, Calif., the Naval Health Research Center, San Diego, Calif., and the Naval
Medical Research Institute/Toxicology Detachment, Wright Patterson Air Force Base, Ohio.
This work was completed while he was at the latter laboratory. In addition, he has done
research and taught part-time at San Diego State University, San Diego; is currently an
Assistant Clinical Professor of Pharmacology and Toxicology at Wright State University
School of Medicine, Dayton, Ohio; and has worked collaboratively with the Bob Hippie
Laboratory for Cancer Research of the Wright State University School of Medicine.
Dr. Hilderbrand is a member of the New York Academy of Sciences and the American
Association for the Advancement of Science. His current major research interests are the
effects of toxic chemicals on hematopoietic, renal, and neural tissue. Past research has
included rapid identification of infectious organisms, biochemical changes associated with
human endurance performance, binding of prostaglandins to receptors on adipocytes, and
studies of the natural occurrence of phosphonates.
CONTRIBUTORS
Timothy A. Calamari, Jr. Thomas 0. Henderson
Supervisor Research Chemist Department of Biological Chemistry
Southern Regional Research Center University of Illinois Medical Center
New Orleans, Louisiana Chicago, Illinois
Richard L. Hilderbrand
George L. Drake, Jr.
Lieutenant Commander
Supervisor Research Chemist
Medical Service Corps
Southern Regional Research Center
U.S. Navy
New Orleans, Louisiana
Biochemist
Naval Biosciences Laboratory
Oakland, California
Robert Engel
Professor of Chemistry and Biochemistry
Raymond R. Martodam
Department of Chemistry
Staff Scientist
Queens College
Miami Valley Laboratories
The City University of New York
Procter and Gamble Company
Flushing, New York
Cincinnati, Ohio
Marion D. Francis Joseph Donald Smith
Senior Scientist Assistant Professor of Chemistry
Miami Valley Laboratories Department of Chemistry
Procter and Gamble Company Southeastern Massachusetts University
Cincinnati, Ohio North Dartmouth, Massachusetts
TABLE OF CONTENTS
Chapter 1
Foreword � 1
Richard L. Hilderbrand
Chapter 2
Phosphonic Acids in Nature � 5
Richard L. Hilderbrand and Thomas 0. Henderson
Chapter 3
Metabolism of Phosphonates � 31
Joseph Donald Smith
Chapter 4
Chemical, Biochemical, and Medicinal Properties of the Diphosphonates � 55
Marion D. Francis and Raymond R. Martodam
Chapter 5
Phosphonic Acids and Phosphonates as Antimetabolites � 97
Robert Engel
Chapter 6
The Effects of Synthetic Phosphonates on Living Systems � 139
Richard L. Hilderbrand
Chapter 7
Industrial Uses of Phosphonates � 171
George L. Drake, Jr. and Timothy A. Calamari, Jr.
Index � 195
1
Chapter 1
FOREWORD
Richard L. Hilderbrand*
TABLE OF CONTENTS
I.� Foreword � 2
References � 3
* Dr. Hilderbrand is an officer or employee of the U.S. Government. This work was prepared as part of his
official duties. Under 17 U.S.C. 105.
2� The Role of Phosphonates in Living Systems
I. FOREWORD
Organic compounds of phosphorus play an integral role in the biochemical processes of
all living systems.. These life processes require orthophosphate (PO4) as a primary con-
stituent of nucleic acids, phospholipids, and phosphorylated proteins and carbohydrates. Of
equal importance is the use of phosphate to generate high energy phosphate bonds whose
energy is either used for synthetic processes or for production of other types of energy. In
addition, phosphate provides buffering capacity, imparts solubility in aqueous solutions to
organic molecules, precipitates with calcium to form the insoluble hydroxylapatites required
in bone, and can provide a high concentration of negative charge within a given molecular
dimension.' Phosphate esters are relatively stable in aqueous solutions at physiological pH
but will readily hydrolyze when appropriate enzymes are present. Thus, phosphate is uniquely
suited to provide the properties necessary to maintain the mosaic of biochemical reactions
occurring within a living organism.
All phosphorus accessible to living organisms occurs in phosphate minerals as ortho-
phosphates. The phosphorus atom occurs at the + 5 level of oxidation with four oxygen
atoms bonded to the phosphorus in a tetrahedral structure. The organophosphates which
occur naturally in a living system are usually oxygen esters, diesters, or anhydrides of
phosphoric acid. There are rather infrequent exceptions to this bonding of phosphates in
living systems. One exception is the natural occurrence of the carbon to phosphorus (C—P)
bond in the phosphonate class of organophosphates. Although phosphate had long been
recognized as crucial to life processes, it was not until 1947 that Chavane,2 a chemist involved
in synthesizing phosphonates, observed that, since the C—P bond was stable, there was a
possibility for the occurrence of phosphonates in nature. The actual identification of a
naturally occurring phosphonate finally came in 1959 by Horiguchi and Kandatsu,3 who
identified 2-aminoethylphosphonic acid (AEP) in an amino acid extract from an hydrolysate
of rumen protozoal lipid. Phosphonates have subsequently been shown to occur naturally
in a variety of organisms and several metabolic processes involving phosphonates have been
elucidated.
The study of synthetic organophosphorus molecules was initiated by Lassaigne in 1820
with the esterification of alcohols and phosphoric acid. In the late 19th and early 20th
centuries, A. E. Arbuzov conducted research on the chemistry of trivalent phosphorus
compounds. From this work came the well-known Michaelis-Arbuzov reaction, for the
synthesis of the C—P bond, and a number of compounds which were forerunners of the
insecticides in use today.4
The chemistry of phosphonates has developed more slowly than that of phosphate because
of the difficulty of synthesizing the C—P bond and the wide availability of, and information
on, orthophosphate and phosphate esters. With recognition of the unique chemical properties
of phosphonates, commercial interest is increasing markedly.' The types of phosphonates
of potential or actual industrial interest include catalysts, lubricant additives, flame retardants,
surfactants, corrosion inhibitors, and plasticizers. In addition, commercial interest has de-
veloped in the use of phosphonates as insecticides, plant growth effectors, and health care
products.
The chemical properties of the phosphonates, mechanisms of synthesis, and various an-
alytical methodologies will be presented as required for each topic. The initial chapters
include a summary of the natural occurrence of phosphonate and the information available
on the metabolism of those compounds. The latter chapters of the book are descriptions of
specific biological effects and uses of various types of synthetic phosphonates, including
industrial materials. The information on industrial processes is included to show the variety
of ways in which phosphonates can affect not only life processes, but our life style. In
addition, the industrial applications can indirectly affect our life processes by inadvertent
3
environmental or occupational exposure, thus generating the necessity of our knowing how
phosphonates are used industrially. Information on both naturally occurring organophos-
phonates and synthetically produced organophosphonates will be included.
REFERENCES
1. Katchman, B. J., Phosphates in life processes, in Phosphorus and its Compounds, Vol. 2, Van Wazer,
J. R., Ed., Wiley-Interscience, New York, 1961, chap. 20.
2. Chavane, M. V., Synthese de quelques acides phosphoniques amines de formule generale H3W-(CH2).-
POH, Compt. Rend., 224, 406, 1947.
3. Horiguchi, M. and Kandatsu, M., Isolation of 2-aminoethane phosphonic acid from rumen protozoa,
Nature (London), 184, 901, 1959.
4. O'Brien, R. D., Toxic Phosphorus Esters, Academic Press, New York, 1960, chap. 1.
5. Chadwick, D. H. and Watt, R. S., Manufacture of phosphate esters and organic phosphorus compounds,
in Phosphorus and its Compounds, Vol. 2, Van Wazer, J. R., Ed., Wiley-Interscience, New York, 1961,
1272.