ously (Section I I , C ) , the metabolic inhibitors to be considered briefly in this section are not polypeptides according to the definition (1) used here.
For the purpose of this category, simple inhibitory compounds with pep
tide linkages, such as acetyl and benzoyl derivatives of amino acids, are excluded.
Moreover, in certain instances, these agents exhibit biological activity for reasons other than their peptidic nature. The analogues of folic acid, for example, are peptides of glutamic acid, yet there are several classes of small-molecule, nonpeptide inhibitors of folic acid (817) which are equally effective in certain biological systems. Such compounds, as well as the analogues of folic acid, exhibit "classic" metabolite-antimetabolite an
tagonisms.
In other instances (e.g., peptides of aromatic nitrogen mustards), the peptide structure serves as a "carrier" of a cytotoxic moiety. These in
hibitors act as alkylating agents, rather than by virtue of the peptide residues.
More detailed discussions of these classes of inhibitors will be found in other chapters of the present volume and elsewhere in other reviews
(68, 818).
A. Folic Acid Analogues
Following the suggestion (819, 320) that the "acceleration" phenomenon in the viscera and bone marrow of patients with acute leukemia treated with pteroyltriglutamic acid and observations on the biology of experi
mental P G A deficiency in rats might be employed to advantage in the chemotherapy of the acute leukemias of childhood, either by combined treatment with P G A (or its conjugates) and nitrogen mustard or irradia
tion or by the direct use (320-822) of PGA antagonists (323), these in
hibitors have been studied extensively for many reasons, some of which are unrelated to the problems of neoplasia or acute leukemia. The useful
ness of these agents in the latter area has been reviewed by Farber et. al.
(63). The parent member of this class of inhibitors is
4-aminopteroyl-NHj,
( X V I )
glutamic acid (aminopterin, X V I ) , in which the 4-hydroxyl group of PGA is replaced by an amino group.
Since these inhibitors are reviewed elsewhere in this volume (Chapter 13, T. H. Jukes and H. P. Broquist, "Sulfonamides and Folic Acid Anta
gonists") they need not be considered further here.
B. Peptides of Aromatic Nitrogen Mustards
The peptide moiety of the compounds considered in this section serves as a carrier of the inhibitory bis(2-chloroethyl)amine (nitrogen mustard) residue and not as a metabolic inhibitor itself. Such compounds deserve mention here since they represent a relatively new type of growth inhibitor.
The concept that more selective action of the nitrogen mustards on neoplastic tissue might be achieved by linkage of the nitrogen mustard residue to carrier molecules that would either have a more favorable pharmacological distribution or would be enzymically activated at the proper biological site has been proposed and investigated in several labora
tories {824-335). The nitrogen mustard derivative of phenylalanine, p-di-(2-chloroethyl)aminophenylalanine ( X V I I ) , has been a particularly active compound of this kind. Bergel and Stock {827) prepared the L-isomer of ( X V I I ) (melphalan), and Larionov and his associates {832) and the British group {327) reported the DL-form (sarcolysin, merphalan).
In an attempt to improve the selectivity or the therapeutic index of ( X V I I ) , a number of peptide derivatives have been prepared. Subsequent to a report of the synthesis of some ΛΓ-benzoyl dipeptides of merphalan {386), Bergel and co-workers have described the preparation of several di- and tripeptides and one tetrapeptide of melphalan {837). The tri
peptide analogue ( X V I I I ) is an example of some of the compounds re
ported.
NHJJ
(XVII)
I^NHCHRaCONHCHI^CONHÇHCHa—
COOC2H5
NiCI^CHjjCl);,
(XVIII)
Larionov and his colleagues (338-340) have reported the antitumor properties of peptides of iV-formylsarcolysin and iV-aeetylsareolysin. The attachment of amino acids to sarcolysin through a peptide bond afforded compounds whose spectrum of experimental antitumor activity differs from that of sarcolysin and varies with different amino acids. Among tripeptide derivatives of sarcolysin, the spectrum and potency of anti
tumor activity varies with the terminal amino acid and the sequence of amino acids in the peptide. Several of these derivatives of sarcolysin exhibit significant activity in human neoplasia (334, 840). The biological investigation of several peptides of phenylalkanoic acid nitrogen mustards has also been reported (340). Fu (340a) has reported the preparation of the L- and D-isomers of p-[V-bis(2-chloroethyl)]-aminobenzoylglutamic acid, a nitrogen mustard analogue of the side chain of folic acid.
Both the British (837) and the Russian (340) groups have concluded that the nature of the peptide carrier of these aromatic nitrogen mustards has a profound effect on biological activity. Further details on the inhibi
tory properties of nitrogen mustard derivatives will be found in Volume I I in the chapter entitled "Alkylating Agents" by J. M . Johnson and F. Bergel.
C. Pantothenic Acid Analogues
Pantothenic acid ( X I X ) , a growth factor widely distributed in nature, is a peptide of β-alanine and pantoic acid. Several analogues have been
H O C H2C ( C H3) 2C H O H C O N H ( C H , ) 2C O O H
( X I X )
prepared by modification of either or both the β-alanine and pantoic acid moieties. Such analogues in general interfere with the metabolic activity of pantothenic acid, rather than by displacement of the metabolite, and with few exceptions exhibit activity only in pantothenate-dependent systems.
Inhibition of the synthesis of pantothenic acid from its precursors can be accomplished with much simpler structures, e.g., cysteic acid in E. coli systems, via interference with the enzymic decarboxylation of aspartic acid (341). Cohen et al. (842) described a third class of inhibitor, D-[2-(pantoylamino)ethylsulfonoJ-4-nitroanilide ( X X ) , which interferes with the metabolic activity of coenzyme A .
H O C H2C ( C H8)2C H O H C O N H ( C H2)2S 02N H
( X X )
The antagonists of pantothenic acid have been reviewed by Woolley (843), Martin (844), and, more recently, by Kaiser (845).
D. Glutathione Analogues
Glutathione is the tripeptide 7-L-glutamyl-L-cysteinylglycine ( X X I ) , and it is the coenzyme of the glyoxylase reaction, which converts
methyl-H O O C C methyl-H ( C methyl-H2)2C O N H C H C O N H C H2C O O H I I
N H2 C H2
( X X I )
glyoxal into lactic acid (846). The reaction is inhibited by cysteinylglycine (847-849), #-methylglutathione (848), and certain other tripeptides, such as 7-DL-glutamyl-DL-alanylglycine (348). The best inhibitors are S-(N-ethylsuccinyl) -glutathione and ophthalmic acid (350, 851). Ophthalmic acid, 7-glutamyl-a-amino-n-butyrylglycine ( X X I I ) , is a naturally occurring
H O O C C H i C H ^ ^ O N H C H C O N H C H i j C O O H
I I
N H2 C H2
I
C H3
( X X I I )
tripeptide isolated from the lens of the calf, and has been synthesized (352). It is a competitive inhibitor of glutathione, differing in structure only in that the thiol group of glutathione is replaced by methyl.
E. Synthetic Antibacterial Tripeptides
Of the eight possible isomers of valylvalylvaline, only the LLD-form was inhibitory to several bacteria (358). The other isomers and related peptide derivatives were inactive at much higher concentrations.