Peptides dipeptide mimics

The benzene ring has been proposed as an isosteric replacement in a dipeptide to enforce either the tram l1 1 or the cis conformation 312>31 (Scheme 1). Similarly, 2-(amino-methyl)pyrrole-l-acetic acid (8, R = H) has been proposed as a cis peptide bond mimic,141 having the same number of atoms between the amino and carboxylic acid functions as in a dipeptide. Several other amino- and carboxy-substituted aromatic structures have been used as spacers in peptides 2-, 3-, and 4-aminobenzoic acids (Abz, e.g., 7), 2-, 3-, and 4-(amino-methyl)benzoic acids (Amb, e.g., 2), 2-, 3-, and 4-(aminophenyl)acetic acids (APha, e.g., 5), 2- (4), 3-, and 4-(aminomethylphenyl)acetic acid (Ampa), (aminomethyl)pyrrole-, -thiophene-, and -furancarboxylic acids 6, (aminomethyl)pyrrole- 8 and -thienylacetic acids, and aminobiphenylcarboxylic acids. 

Spiro lactam 15 (Scheme 9), a dipeptide mimic with C (/)<-+Na(/ + l) cyclization, was used to replace the Pro-Tyr segment of an immunogenic peptide. 69 Comprehensive conformational analysis led to the conclusion that a type-II p-turn conformation was adopted in solution. 

Two general routes to a new class of dipeptide mimics, the fluoroolefin dipeptide isosteres, will be presented. They allow the preparation of compounds of formula 2 with a wide variety of residues R, and r3 in racemic or enantiomerically pure form. Some of the mimics have been introduced into small peptides of biological interest. Some preliminary results will also be discussed. 

Peptides containing the Fluoroolefin Dipeptide Mimic and their Biological Activity... 

Fluorinated analogues of substrate mimics of dipeptides or of phosphates in which the peptidic or phosphate bond is nonscissile. 

The Z-alkene isostere mimics the cis-amide bond conformation. Its molecular volume and log p values are almost identical to those of the E-isostere (Table 1). Its use in bioactive peptides is very limited, probably because of the synthetic challenge involved. One study reports the migration of the double bond to the a,(3-position in an enkephalin analogue. 4 The Z-alkene in the Alat t[Z, CH=CH]Pro dipeptide isostere, however, was reported to be stable towards isomerization.1 1X1 orf/to-Substituted aromatic or tetrazole rings have been used more frequently as ds-amide bond mimics. 

As a key feature of the TASP approach, the template is designed to direct and reinforce the folding of the covalently attached secondary structure elements in the predetermined tertiary structures (Scheme 1), e.g. a four a-helical bundle. The major purpose of artificial turn-inducing mimics is to constrain, when incorporated at the appropriate location, the peptide chain into a semi-rigid, defined, spatial arrangement. 39 8-(Aminomethyl)-5,6,7,8-tetrahydro-2-naphthoic acid (Amhn) is designed to substitute for the central dipeptide unit of a reverse turn and is prepared in a five-step procedure starting from commercially available 4-phen-ylbutanoic acid 40 (Scheme 3). 

As illustrated by the synthesis of 13, which can be viewed as a Gly-Hse (Hse = homoserine) mimic (Scheme 1.2.4), aminals of the general structure 11 serve as versatile educts for the preparation of pipecolyl-dipeptide analogs with fixed anti-peptide geometry. The stereochemistry of compound 13 was determined unambiguously by 2D NOESY NMR spectroscopy and is in accordance with a re-... 

In 2003, a new Sml2-mediated carbon carbon bond-forming reaction was reported by Skrydstrup for the direct synthesis of peptide mimics for evaluation as protease inhibitors.90 For example, the low-temperature coupling of 4-thiopyridyl ester 100, derived from Cbz-protected phenylalanine, with the dipeptide acrylamide 101 gave the peptide analogue 102 in a 61% yield (Scheme 7.43). Ketone 102 represents a ketomethylene isostere of the tetra-peptide Phe Gly Leu Phe. Ketomethylene isosteres and the corresponding reduced analogues, hydroxyethylene isosteres, represent important and pharmaceutically relevant classes of protease inhibitors.91,92... 

Hamuro et al. chose cyclic hexapeptides to mimic the "arms" of the antibody because they can he modified so as to link up easily with the core scaffold, and because they form hairpin loops "The peptide loop was based on a cyclic hexapeptide in which two residues were replaced by a 3-aminomethylbenzoyl (3amb) dipeptide analogue containing a 5-amino substituent for facile hnkage to the scaffold" (p. 2681). The recipe for... 

By comparison of the calculated electrostatic potentials (77) of trans-2-butene and 2-fluoro-2(Z)-butene with N-methyl acetamide as simple models of the peptidic bond and its isosteres (see figure 1) the fluoroolefin clearly is the better replacement of the amide bond, since it not only mimics its steric but also, at least in part, its electronic feature. Calculating dipole moments Abraham (73) came to similar results, but attempts to synthesize the corresponding dipeptide isostere 2 have been until now unsuccesful (14). As part of our ongoing program in fluoroorganic chemistry we developed two general methods for the preparation of these compounds. 

We have established two routes to a new class of peptide mimics, the fluoroolefin dipeptide isosteres. By appropriate selection of the precursors they allow the preparation of anaolgues of dipeptidic combinations of aminoacids bearing no other functionalities in their side chains, e.g. Gly, Ala, Val, Phe, Pro. 

As mentioned in Volume 13 of these Reports, 4-oxoazetidin-2-yl phosphonates and phosphinates (19) can be prepared by Arbusov-like reactions between P compounds and 4-acetoxyazetidin-2-one (20). Acid hydrolysis of (19) yields phosphono- and phosphino-aspartic acids (21) which can be converted into peptides with antibacterial activity. Diastereomeric mixtures of phosphono-dipeptides, which can be prepared from racemic dialkyl 1 -aminoalkylphosphonates, can be separated by ion-exchange chromatography. It appears that it is easier to synthesize phosphonodipeptides from these phosphonates as their P-dialkyl esters rather than as the free phosphonic acids. Phosphonic acid analogues of A-Cbz-alanine and -phenylalanine can be converted into ester and amide fluoridates, e.g., (22, R = OMe or NHCHMeg). These fluoridates are the most potent inhibitors of elastase and chymotrypsin yet reported and seem to mimic the natural substrates of these enzymes. ... 

An artificial ribozyme mimics this translation step of the ribosome. The spedlity of this selected ribozyme is based on the recognition of an adenosine moiety of the amino acid ester and allows the utilization of leucine- and phenylalanine- as weU as methionine-derivatized substrates. This tolerance for various amino acids indicates the possibility of selecting more general ribozymes for protein synthesis. Furthermore, a related ribozyme efficiently catalyses the synthesis of -30 different dipeptides from an aminoacyl-adenylate substrate. Ribozyme-mediated synthesis of uncoded peptides might have been an important step in the transition from a RNA to a peptide world before the anergence of the ribosome. ... 

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