Synthesis, Occurrence, and Action of Biologically Active Polypeptides. The Peptides, Volume 2

652 Pages·1966·30.101 MB·English

by  Eberhard Schröder and Klaus Lübke (Auth.)

The Peptides
BY
EBERHARD SCHRÖDER
AND
KLAUS LÜBKE
HAUPTLABORATORIUM DER SCHERING AG
WEST BERLIN, GERMANY
Translated by Erhard Gross
NATIONAL INSTITUTES OF HEALTH
BETHESDA, MARYLAND
VOLUME II
Synthesis, Occurrence, and Action of
Biologically Active Polypeptides
1966
ACADEMIC PRESS New York and London
COPYRIGHT© 1966, BY ACADEMIC PRESS INC.
ALL RIGHTS RESERVED.
NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM,
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LIBRARY OF CONGRESS CATALOG CARD NUMBER: 65-22760
PRINTED IN THE UNITED STATES OF AMERICA
PREFACE
After the isolation, structural elucidation, and synthesis of oxytocin
by du Vigneaud the synthesis and chemical modification of biologically
active polypeptides became interesting areas of peptide chemistry. The
number of newly discovered, naturally occurring peptides of high bio-
logical activity and their growing lists of analogues made it desirable to
review the results of the last decade.
In Volume I of "The Peptides" synthetic methods were described. In
Volume II, subtitled "Synthesis, Occurrence, and Action of Biologically
Active Polypeptides," the synthesis of biologically active polypeptides and
analogues is described. In many instances, in addition to the description
of preparative details, synthetic routes are presented schematically. Ex-
tensive tables allow for the accommodation of presently known analogues
and their activities. In addition to the synthesis, the isolation, structural
elucidation, and action of biologically active peptides are discussed
briefly. The kinin-like peptides are presently in the forefront of interest
and have received a somewhat broader treatment. Thus, chemists will be
assisted in gaining an insight into the biological significance of poly-
peptides.
In order that the reader have a review of the entire literature on
peptides, a complete bibliography, through 1964, has been included in
both volumes. In addition, publications which appeared by the middle of
1965 were added to the bibliography of this volume.
We should like to thank Schering AG for making this work possible.
We are grateful to Dr. Gibian, with whom we started work in the peptide
field several years ago, for his encouragement and support.
We are indebted to Professor Dr. Langecker for critically review-
ing the chapter on biology. We should also like to acknowledge the
assistance of our co-workers in preparing this work.
Finally, we must express our gratitude to Dr. E. Gross who carried
out the voluminous task of translating this monograph.
E. SCHRÖDER
K. LÜBKE
February, 1966
v
Contents of Volume I
Methods of Peptide Synthesis
Introduction
Amino-Protecting Groups
Carboxyl-Protecting Groups
Formation of the Peptide Bond
Amino Acids
The Synthesis of Cyclic Peptides
Depsipeptides
Peptoids
The Plastein Reaction
Solid Phase Peptide Synthesis
Problems of Racemization
Bibliography
Author Index — Subject Index
IX
Nomenclature of Amino Acids and Peptides
The nomenclature that we have used for amino acids, peptides, and
peptide hormones is based essentially on the proposals by:
(1) E. Brand and J. T. Edsall, Ann. Rev. Biochem. 16, 224 (1947).
(2) E. Bricas and C. Fromageot, Advan. Protein Chem. 8, 1 (1953).
(3) I. M. Goodman and G. W. Kenner, Advan. Protein Chem. 12, 465
(1957).
(4) R. Schwyzer, Chimia (Aarau) 12, 53 (1958).
(5) Committee on Abbreviations of the American Society of Biological
Chemists, 1959.
(6) IUPAC, Section of Biological Chemistry, Nomenclature Commission
1960; cf. J. Biol. Chem. 237, 1381 (1962).
(7) J. P. Greenstein and M. Winitz, "The Chemistry of the Amino Acids."
Wiley, New York, 1960
(8) R. Schwyzer, J. Rudinger, E. Wünsch, and G. T. Young, Suggestions
in the "Fifth European Peptide Symposium" (G. T. Young, ed.),
p. 261. Macmillan (Pergamon), New York, 1963.
A. ABBREVIATIONS OF AMINO ACIDS
(1) Individual amino acids in the text are mentioned by their full
names. Abbreviations are used only in tables, reaction schemes,
etc., and for the presentation of peptides.
(2) Except for a few cases, the abbreviations consist of the first
three letters of the trivial name (cf. Table on Nomenclature at
the end of this section). If there is no trivial name, the chemical
name is used in its Anglo-Saxon form and an abbreviation is
formed from the first letters of the syllables. Structurally related
amino acids have related abbreviations. The first letter is always
capitalized, in the peptide chain likewise.
(3) The abbreviation represents the amino acid residue. The formu-
lation of a free amino acid or of a free peptide is unequivocal
only when it terminates in an H— at the amino group or an
xi
Xll NOMENCLATURE
—OH at the carboxyl group. The amino group always appears
to the left, the carboxyl group to the right. Side chains are
accommodated above or below the line.
ÇH ÇH3
3
NH-CH-CO = Ala H-HN-CH-CO-OH = H-Ala-OH
H-Val-Leu-Ala-OH
Where the amino acid chain contains parts of an uncertain sequence
the symbols are separated by a comma. The unknown amino acid
sequence is put in parentheses:
H-Pro-Val-Leu-(Ala, Glu, Asp, Pro)-Arg-Gly-OH
(4) Additional designations are treated as follows:
(a) Amino acids without «-amino group or with an additional
amino group in an unusual position are further characterized
by the designation of this position:
/?-AIa γ-Abu β,γ-Abu
(b) In the case of isomeric amino acids the iso compound, in
analogy to Heu, is abbreviated by adding the prefix I, the
unbranched form, accordingly, by adding the prefix N:
Leu lieu Val Nval
(c) Hydroxyamino acids carry the prefix "Hy" unless they have
their own trivial name:
Hypro Hylys
The position of the hydroxy group can be specified by a preceding
Greek letter: δ-Hylys
(d) No abbreviation has been introduced for "homo" (one
more CH group ) and "nor" ( one CH group less ) :
2 2
Homoarg Norarg
(e) The substituent in 2V-substituted amino acids is placed before
the amino acid in the form of its commonly used abbrevia-
tion separated by a period if no trivial name is used. The
amino substitution can be designated clearly by the prefix N:
JV-methylvaline = Me· Val or N-Me*Val
NOMENCLATURE xiii
C-Substituted amino acids are always distinguished by a
preceding C. The C atom will eventually have to be desig-
nated more closely:
C-Ph-Gly Ca-MeAla
(f) Cys stands for cysteine, (Cys) for cystine. Cystine peptides
2
are best expressed in two lines, e.g.:
cystinylbis- (valylleucine):
H-(Cys) -bis-(Val-Leu-OH) or H-(Cys) -(Val-Leu-OH) or H-Cys-Val-Leu-OH
2 2 2
H-Cys-Val-Leu-OH
(5) For the designation of the optical activity the configuration is
placed before the amino acid, separated by a hyphen.
The uncertainty about the configuration of an amino acid should
be expressed by a question mark in the sequence of the peptide:
H-L-Me · Leu-OH H-L-Ala-D-Val-OH H-L-Ala- ? -Leu-D-Val-OH
No designation always means the L-form.
Amino acids with two centers of asymmetry are expressed as follows:
D-Alloisoleucine D-alleu L-Allohypro L-aHypro
The amino acid is considered as a unit and will be preceded by all
structural and configurational designations, e.g.:
allo = a erythro = e threo = t meso = m
B. ABBREVIATIONS FOR THE BLOCKING GROUPS
Of the most widely known abbreviations for the carbobenzoxy group,
Cbo- and Z-, Cbo will be used. Carbobenzoxy groups with substituents
in the p-position will be designated by the substituents preceding them.
Since for the p-phenylazocarbobenzoxy and the p-methoxyphenylazo-
carbobenzoxy groups no abbreviation derived from Cbo has been intro-
duced, the present exclusively used designations PZ and MZ will be
employed.
The abbreviations for N-acyl-, N-aryl-, and the carboxyl-protecting
groups (cf. Tables II and III) are based essentially on those most com-
monly used in the literature. Protecting groups, derived from others by
substitution, have no abbreviations of their own ( e.g. OBzl and OBzlN0
2
for benzyl and p-nitrobenzyl esters).
XIV NOMENCLATURE
C. PRESENTATION OF SUBSTITUTED PEPTIDES
(1) The abbreviated expression for peptide derivatives consisting of
monoaminomonocarboxylic acids is unequivocal, e.g.:
Cbo-L-Val-L-Pro-OMe BOC-L-Val-L-Pro-OH H-L-Val-L-Pro-OBzl
Salt formation at the amino group:
H-Ala-OMeHCl or H®-Ala-OMe Cle
Salt formation at the carboxyl group:
Cbo-Ala-ONa or Cbo-Ala-OeNae
Cbo-L-Phe-L-Ser-OH-dicyclohexylamine
but
Cbo-L-Phe-L-Ser-O-dicyclohexylammonium
Inner salt formation:
H +-Ala-0-
2
(2) Two different possibilities exist for bifunctional amino acids:
(a) One line expression:
The substituent of the ω-function is placed in parentheses directly
behind the amino acid. The nature of the bond is clear from the abbrevia-
tion used and from the amino acid.
(b) Dual line expression:
It is clearer and will always be used when reaction schemes are
presented. The substituent at the ω-function will be placed above, less
frequently below.
Bzl NO,
I I
Cbo-L-Ser(Bzl)-L-Arg(N0)-OMe or Cbo-L-Ser-L-Arg-OMe
2
BOC NH
I | 22
Trit-L-Lys(BOC)-L-Asp(NH)-NH or Trit-L-Lys-L-Asp-NH
2 2 2
(c) In addition to these abbreviation principles, the following
more detailed formulations may be used equally well:
Na-Trit-Ny-BOC-L-Lys-L-Asp(NH )
2 2
(d) Salt formation at the ω-function can be expressed ac-
cordingly:
NOMENCLATURE XV
6
t
Cbo- L-Cys (Ag)-L-Phe-OMe Cbo- L-Cys- L-Phe-OMe
H?
H-L-Arg(HCl)-L-Glu-NH2 H-L-Arg-L-Glu-NH Cl9
2
ONa
I
Cbo-L-Glu(ONa)-L-Ala-OMe Cbo-L-Glu-L-Ala-OMe
The salt-forming compound is more frequently placed
behind the peptide separated by a period:
H-L-Val-L-Leu-OMe· picrate
H-L-Arg-L-Leu-OMe-2 HC1
(3) The following abbreviations result for trifunctional amino acids:
Cbo
y-Hylys(Cbo,y-Me)-OMe or y-Hylys(y-Me)-OMe
N€-Cbo-0-Methyl-y-hydroxylysine methyl ester
(4) In the case of tetrafunctional amino acids a clear expression in
a single line is not possible. Therefore the following expression
in several lines is proposed. It can also be used for cystine
derivatives:
Cbo OMe BOC OMe Cbo. .OH
Lan /DaP\ *Cys)2
Tos^ OBzl Cbo^ OMe Trit^ ^OMe
(5) «,ω-Peptides of monoaminodicarboxylic acids and diaminomono-
carboxylic acids, respectively, are expressed as follows:
(a) In a single line:
Cbo-Glu-α - (Val-OH)-y- (Leu-Ala-OH)
In two lines:
r-Leu-Ala-OH
Cbo-Glu-Val-OH
(b) In a single line:
a - (BOC-Phe)-c- (Cbo-Ala-Val)-Lys-OEt
In two lines:
Cbo-Ala-Val-i
BOC-Phe-Lys-OEt
XVI NOMENCLATURE
(c) In a single line:
a-(Cbo-Val)-e-(Cbo-Glu-a-OMe-y-)-Lys-OMe
In two lines:
Cbo-Glu-OMe
Cbo-Val-Lys-OMe
D. CLASSIFICATION OF PEPTIDES
The peptides will be divided into two main groups: homomeric
peptides and heteromeric peptides.
(1) Homomeric Peptides
In the group of homomeric peptides are all the compounds which
on hydrolysis yield amino acids exclusively. On the basis of
amino acid order and the type of linkages the following pos-
sibilities result:
(a) Homodetic linear homomeric peptides: Peptide bonds
only between carboxyl and amino groups, irrespective of
a- or ω-bond, e.g.:
H-Asp-Arg-Val-Tyr-Val-His-Pro-Phe-OH
(b) Heterodetic linear homomeric peptides: O-Peptides of
serine, threonine, and other ω-hydroxy-a-amino acids or
of S-peptides of cysteine:
Cbo-Val-Phe-O Cbo-Val-Phe-S
H-Pro-Ser-Glu-OH H-Pro-Cys-Glu-OH
(c) Homodetic cyclic homomeric peptides:
9 10 1 2 3
Val | H Qrn 1 H Leu 1 H P-Phe | H pro
Pro -ta-Pheh« Leu h« Orn h« Val
8 7 6 5 4
or
I—Val-Orn-Leu-D-Phe-Pro-Val-Orn-Leu-D-Phe-Pro—i
The formulation with boxes uses arrows to indicate the direction
of the peptide bonds (CO-»NH).
Amino acids in the ring should be numbered in such a way that the
amino acid first in alphabetical order is assigned number 1 and additional