Table Of ContentBIOMIMETIC
POLYMERS
BIOMIMETIC
POLYMERS
Edited by
Charles G. Gebelein
Youngstown Slate University
Youngstown, Ohio
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloging-In-Publication Data
Blomlmetlc polymers I edited by Charles G. Gebeleln.
p. cm.
Based on the proceedings of the American Chemical Society
Symposium on Enzyme Mimetic and Related Polymers. held at the Third
Chemical Congress of North America. ~uly 5-8. 1988. In Toronto.
Ontario. Canada.
Includes bibliographical references and Index.
1. Bloalmetlc polymers--Congresses. I. Gebeleln. Charles G.
Q0382.B47B56 1990
547.7--dc20 90-46930
CIP
Based on the proceedings of the American Chemical Society Symposium on Enzyme
Mimetic and Related Polymers, held at the Third Chemical Congress of North America,
July 5-8, 1988, in Toronto, Ontario, Canada
ISBN-13: 978-14612-7913-6 e-1SBN-13: 978-1-4613-0657-3
DOl: 10.1007/978-14613-0657-3
© 1990 Plenum Press, New York
Softcover reprint of the hardcover 1s t edition 1990
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
PREFACE
The term biomimetic is comparatively new on the chemical scene, but
the concept has been utilized by chemists for many years. Furthermore,
the basic idea of making a synthetic material that can imitate the func
tions of natural materials probably could be traced back into antiquity.
From the dawn of creation, people have probably attempted to duplicate or
modify the activities of the natural world. (One can even find allusions
to these attempts in the Bible; e.g., Genesis 30.)
The term "mimetic" means to imitate or mimic. The word "mimic" means
to copy closely, or to imitate accurately. Biomimetic, which has not yet
entered most dictionaries, means to imitate or mimic some specific bio
logical function. Usually, the objective of biomimetics is to form some
useful material without the need of utilizing living systems. In a simi
lar manner, the term biomimetic polymers means creating synthetic poly
mers which imitate the activity of natural bioactive polymers. This is a
major advance in polymer chemistry because the natural bioactive polymers
are the basis of life itself. Thus, biomimetic polymers imitate the life
process in many ways. This present volume delineates some of the recent
progress being made in this vast field of biomimetic polymers.
Chemists have been making biomimetic polymers for more than fifty
years, although this term wasn't used in the early investigations. The
pioneering work of Overberger and others helped open new vistas of bio
active polymer research in the early 1950s. This was followed by intensi
fied research in the 1960s and 197Qs, lead by Donaruma, Samour, Vogl,
Takemoto, Goodman, Ringsdorf, Levy and others. By the mid-1970s, the
scholarly domain of biomimetic polymers was well established. What re
mained was to translate this research into practical applications. This
effort continues today, but some biomimetic polymers are already showing
promise in several biomedical operations.
In this book, we'll consider a few of the major classes of biomimetic
polymers. The natural bioactive polymers are divided into several classes
and mimics of most are represented herein. Enzymes are possibly the best
know natural bioactive polymer, and the first seven chapters consider
polymers which emulate the catalytic activity of these important polypep
tides. The first two papers describe some organic synthesis reactions
catalyzed by polymeric m~terials. In the first paper, Wolff describes
polymers with chiral cavities and their use in 'organic synthesis. Burdick
and Schaeffer then describe the use of thin films of some biocatalysts,
similar to photographic films, to synthesize some important biochemicals.
The next paper (Mathias, et al.) describes enzyme-like activity for
some simple polymers based on 4-diallylaminopyridine. These polymeric
catalysts were useful in hydrolysis and esterification reactions. Carra
her, et al., describe the synthesis of some potentially bioactive poly-
v
(amino acids) containing platinum or titanium atoms. Zeolites, inorganic
polymers, are then considered as potential biomimetics with various sized
cavities (Herron).
The sixth and seventh papers consider natural polymers whose proper
ties have been modified to give enzyme-like behavior. In the first, Hil
vert, the bioactivity of catalytic antibodies is described; this is an
especially promising biomimetic realm, with dozens of new papers each
year. The second paper (Keyes and Albert) discusses the process of "re
educating" ordinary protein molecules to teach them "new tricks" and make
them act like a regular enzyme.
Heparin, an anionic polysaccharide, is the central polymer in the
next three papers. In the first of these papers, Linhardt and Loganathan
review the chemistry and biological activities of heparin and the hepari
noids. The extracorporeal removal of heparin from the blood is then con
sidered by Yang and Teng. The final paper in this group, Sharma, con
siders the blood compatibility of some potential dialysis-membranes,
derived from poly(vinyl alcohol), and containing heparin-like polymers.
The membrane theme continues in the paper by Imanishi and Kimura, who
consider synthetic polypeptides as membrane compartment polymers for the
enkephalins. Penczek and Klosinski then describe synthetic versions of
two important classes of bioactive polymers, the teichoic acids (found in
the cell walls of many bacteria) and the nucleic acids. These analogs are
based on phosphates and related polymeric systems. The synthetic teichoic
acids permit the separation of different ions from mixtures. The synthe
tic nucleic acids are amenable to large scale synthesis, unlike the
oligonucleotides. Takemoto, et al., also describes nucleic acid analogs,
but their methodology is based on polypeptides or poly (ethyleneimines)
with pendant nucleic base units. The final synthetic nucleic acid paper,
Gebelein, discusses some potential medical applications for the nucleic
acid analogs. In the last paper, Wang describes a sustained release sys
tem which uses insulin to increase the growth rate in rats.
Ten of the sixteen papers in this book were presented at a symposium
on "Enzyme Mimetic and Related Polymers," which was organized, by the
Edi tor, for the Third Chemical Congress of North America in Toronto,
Canada, June, 1988. The sponsoring groups were the American Chemical
Society Division of Polymeric Materials:Science and Engineering and the
Biotechnology Secretariat. Their support is gratefully acknowledged. All
of the manuscripts were centrally word-processed by CG ENTERPRISES.
Charles G. Gebelein
vi
CONTENTS
Biomimetic Reactions Using Organized Polymeric Supports 1
G. Wulff
Application of Thin-Film Biocatalysts to Organic Synthesis 15
Brent A. Burdick and James R. Schaeffer
Polymeric Biomimetic Catalysts Based on 4-Diallylaminopyridine 39
Lon J. Mathias, Rajeev A. Vaidya and Gustavo Cei
Synthesis of Platinum and Titanium Poly(Amino Acids) 71
Charles E. Carraher, Jr., Louis G. Tissinger, Isabel Lopez and
Melanie Williams
Zeolites as Inorganic Analogs of Biopolymers 81
Norman Herron
Catalytic Antibodies 95
, Donald Hilvert
Generation of Catalytic Activity by Protein Modification 115
Melvin H. Keyes and David E. Albert
Heparin, Heparinoids and Heparin Oligosaccharides: Structure and
Biological Activities 135
Robert J. Linhardt and Duraikkannu Loganathan
An Immobilized Protamine System for Removing Heparin in
Extracorporeal Blood Circulation 175
Victor C. Yang and Ching-Leou C. Teng
Poly(Vinyl Alcohol)-Polyelectrolyte Blended Membranes-Blood
Compatibility and Permeability Properties 191
A. J. Aleyamma and C. P. Sharma
Condensation of ,Bioactive Compounds into the Membrane Compartment
by Conjugation with Synthetic Polypeptides 203
Yukio Imanishi & Shunsaku Kimura
Polyphosphates Mimicing Structures and Functions of Teichoic Acids 223
Stanislaw Penczek and Pawel Klosinski
Polyphosphates Modeling Elements of Nucleic Acids Structure 243
Stanislaw Penczek and Pawel Klosinski
Nucleic Acid Analogs: Their Specific Interaction and Applicability 253
Kiichi Takemoto, Eiko Mochizuki, Takehiko Wada and Yoshiaki Inaki
Potential Medical Applications of Nucleic Acid Analog polymers 269
Charles G. Gebelein
Growth Rate Increase in Normal Wistar Rats Catalyzed by Insulin 277
Paul W. Wang
Contributors 285
Index 289
viii
BIOBIIETIC REACTIONS USING ORGANIZED POLYKlRIC SUPPORTS
G. Wulff
Institute of Organic Chemistry & Macromolecular Chemistry
University of Dusseldorf, Universitatsstr. 1
D-400 Dusseldorf, F.R.G.
For the preparation of polymeric supports possessing
organized structures, an imprinting procedure on the basis of
template approach was used in crosslinked polymers as well as
in silicas. In this manner, chiral cavities possessing defi
nite shapes and specific arrangements of the functional
groups (corresponding to the templates) were obtained within
the polymer. These polymers could be used for separation of
racemates. Using an analogous procedure, functional groups
with defined cooperativity could be obtained on the surfaces
of silica. Highly reactive 1. 3 .2-dioxaborole moieties were
attached to polymers and were used as reagents for an aldol
type reaction with aldehydes. In this manner, a, ~-dihydroxy
aldehydes, particularly carbohydrates are thus obtained.
IRTRODUCTION
Several attempts have been made during recent years towards designing
catalysts and reagents functioning in a manner similar to enzymes. The
most important problem associated with this approach is to achieve the
right stereochemical arrangement at the active site of the catalyst. One
of the unique characteristics of enzyme catalysis is the binding of the
reacting substrate in a perfectly fitting cavity or cleft of the enzyme
that contains functional groups in the correct stereochemistry for bind
ing, catalysis, and group transfer. This particular feature has been very
difficult to mimic while designing synthetic catalysts.
During the last few years remarkable progress has been achieved in
the design of organic molecules based on molecular recognition. The win
ners of the last year's Nobel Prize, D. J. Cram1 and J.-M. Lehn,2 used
low molecular weight crown ethers or cryptates as the molecular hosts
with cavities for specific binding. It was also possible to fix catalyti
cally active functional groups in the right vicinity to the reacting
groups of the bound substrate. Remarkable enhancement in rate and selec
tivity were observed though turn-over numbers of such reactions were
rather poor. Other hosts have been used in the form of cyclodextrins by
Bender3 and Breslow4 or in the form of certain concave molecules by
Biomimetic Polymers
Edited by C. o. Gebelein
Plenum Press. New York. 1990
Rebek!l and others for performing such type of selective chemical
operations.
Use of polymers as the carrier for the active site of the catalyst
offers another possibility for designing such enzyme-like catalysts.
Basically, the use of polymers makes the system further complicated com
pared to its low molecular weight counterparts, since the support needs
to be made organized. On the other hand the use of polymeric substrates
would offer certain advantages by taking the macromolecular nature of the
enzymes into consideration. In fact many of the unique features of en
zymes are directly related to their polymeric nature. This is particular
ly true for the high cooperativity of the functional groups and the dyna
mic effects such as the induced fit, the allosteric effect, and the
steric strain as exhibited by the enzymes.
For obtaining polymeric catalysts, during the early years, catalyti
cally active groups and binding groups were mostly introduced into poly
mers by copolymerization of the appropriate monomers bearing the desired
functionalities. By this method one obtains a polymer with randomly dis
tributed functional groups (Figure lA). Another possibility involves the
grafting of side chains containing the desired arrangement of functional
groups onto the parent polymer (Figure IB). A third possibility is the
polymerization of monomers with desired arrangement of functional groups.
In this case the groups are localized in the main chain one after an
other, as in some hormone receptors (Figure Ie).
On the contrary, in the case of natural enzymes, the functional
groups responsible for the specificity are located at quite distant
points from each other along the peptide chain and are brought into
spatial relationship as a result of specific folding of the chain. In
this case, both the functional group sequence in the chain and the pep
tide's tertiary structure, i.e., its topochemistry, are decisive (Figure
A B
continu8te words discontlnu8te words
c o
Figure 1. Possible arrangements of functional groups in syn
thetic and natural polymers.B
2
lD). 'l'his type of arrangement has been termed as the "discontinuate word"
by R. Schwyzer.6 In this case complex, three-dimensional steric arrange
ments of the functional groups can be obtained.
This review on biomimetic reactions using organized polymers consists
of two parts. The first part of this article deals with the method deve
loped to prepare defined cavities in polymers by an imprinting procedure
using a template approach. With this method it becomes possible to intro
duce functional groups into the polymer in a discontinuate word arrange
ment. 7-10 Furthermore, the use of the template technique to introduce
functional groups fixed in a defined distance on the surface of a solid
support is described.11,12 The second part of this article deals with the
use of a new polymeric reagent for performing a biomimetic type of
reaction.13,14
MOLECULAR RECOGRITIOR IR POLYKERS PREPARED BY IKPRIRTIRG WITH TEKPLlTES
In order to prepare a polymeric synthetic model of the binding site
of an enzyme, we used a new approach. 7- 1 The functional groups to· be
0
introduced were bound in the form of polymerizable vinyl derivatives to a
suitable template molecule. This monomer was subsequently copolymerized
under appropriate conditions to produce highly crosslinked polymers
having chains in a fixed arrangement. After removal of the template, free
cavities of the type shown in Figure 2 were formed with a shape and a
three dimensional arrangement of functional groups corresponding to that
of the template. The functional groups in this polymer are located at
quite different points along the polymer chain and they are held in
spatial relationship with one another by the crosslinking. This approach
to prepare a cavity differs from those of Cram,1 Lehn,2 and others, who
used crown type compounds to provide a low molecular weight moiety carry
ing the desired stereochemical information. On the other hand, this
method has some similarity With that of Dickey1~ who precipitated silicic
acid in presence of certain templates to produce silicas with affinity
for the concerned templates.
For the optimization of the above technique we have chosen the mono
mer [1] as one of the template monomer.9,16.17 The template is phenyl-a
D-mannopyranoside to which two molecules of 4-vinylbenzeneboronic acids
are bound by diester linkages. The boronic acid groups act as the binding
sites. Since a chiral template was chosen, the accuracy of the steric
arrangement of the binding sites in the cavity could be tested by the
Structure of monomer [1].
3
