Peptides isosteres

Nucleophilic addition reactions to A -monoprotected a-amino aldehydes 1 (Table 20) represent the beginning of the worldwide interest in peptide isosteres for the preparation of certain specific enzyme inhibitors (e.g., aspartylproteinase inhibition). Some examples of this reaction type show a relatively low diastereofacial selectivity, especially when the reactions are per-... 

We have recently reported the synthesis and identification of novel PXR agonists from a library of peptide isosteres [59]. One of the most interesting findings in this... 

Biological applications and utility of fluoroolefin peptide isosteres 5.1. Background... 

The synthesis and utility of fluoroolefin peptide isosteres has previously been reviewed [45], The fluoroolefin isostere preparations summarized below are organized by the synthetic method employed to introduce the fluoroolefin rather than by the dipeptide isostere formed. 

Horner-Emmons. Fluorophosphono dithioacetate (34) in the preparation of fluoroolefin peptide isostere precursors... 

With these promising results, application of metathesis reactions for the construction of the substituted fluoroolefins required in peptide isosteres is potentially very useful. 

BIOLOGICAL APPLICATIONS AND UTILITY OF FLUOROOLEFIN PEPTIDE ISOSTERES... 

Augustyns findings allow the direct comparison of the E and Z forms of the peptide isostere with the parent peptide [61], These authors reported that fluor-oolefin peptide isostere containing compounds were much more potent inhibitors of DPP II but possessed little activity against DPP IV (Table 3). 

P.A. Bartlett, A. Otake, Fluoroalkenes as peptide isosteres Ground state analog inhibitors of thermolysin, J. Org. Chem. 60 (1995) 3107-3111. 

J. Xiao, B. Weisbium, P. Wipf, Electrostatic versus steric effects in peptidomimicry Synthesis and secondary structure analysis of gramicidin S analogues with ( )-alkene peptide isosteres, J. Am. Chem. Soc. 127 (2005) 5742-5743. 

L.G. Boros, B.D. Corte, R.H. Gimi, J.T. Welch, Y. Wu, R.E. Handschumacher, Fluor-oolefin peptide isosteres—tools for controlling peptide conformations. Tetrahedron Lett. 35 (1994) 6033-6036. 

Y. Nakamura, M. Okada, A. Sato, H. Horikawa, M. Koura, A. Saito, T. Taguchi, Stereoselective synthesis of (Z)-fluoroalkenes directed to peptide isosteres Copper mediated reaction of trialkylaluminum with 4,4-difluoro-5-hydroxyallylic alcohol derivatives, Tetrahedron 61 (2005) 5741-5753. 

Peterson olefination chemistry based upon tert-butyl fluoroacetate, generated in situ from the corresponding bromoester, has also been used in the synthesis of peptide isosteres [ 176,177]. Equation (58) shows the crucial early steps in the synthesis of an inhibitor of Dipeptidyl Peptidase IV. 

Kaldor SW, Hammond M, Dressman BA, Frtiz JE, Crowell , Hermann RA. New peptide isosteres useful for the inhibition of HIV—1 protease. Bioorg. Med. Chem. Lett. 1994 4 1385-1390. 

One of the earliest syntheses of r )[CH20] (methyleneoxy) peptide isosteres was reported by Rubini et alJ1,2l These authors used an intermolecular Williamsons reaction between a urethane-protected amino alcohol and tert-butyl bromoacetate (Scheme 1)J1,2] However, this method resulted in low yields and was not applicable to bulky amino acids. Thus, only isosteres containing glycine as the C-terminal component could be synthesized by this method. 

Other modified amino acids have been used as y-turn inducers. For example, Toniolo et al. 21 utilized a reduced peptide isostere (-CH2NH-) moiety and incorporated it into the neurotransmitter tripeptide -Pro-Leu-Gly-. The X-ray diffraction structure of the N-terminal Boc-or Z-protected tripeptide Boc(or Z)-Prot i[CH2NH]Leu-Gly-NH2 2 provides unequivocal proof of the existence of a y-turn (Scheme 3). 

Further discussion and additional references to the synthesis of peptides containing dide-hydro-a-amino acids, reduced peptide isosteres, TV-hydroxy amides and hydrazides, and Ca-tetrasubstituted amino acids including 2,3-methano amino acids can be found in Sections 11.1,10.7,10.8, and 10.3, respectively. 

The cellular effects of FTase inhibition with 3 were observed with concentrations 5000-50,000 higher than the in vitro IC50 for FTase inhibition by carboxylic acid Id. Incomplete hydrolysis of the lactone in vivo could be partially responsible for this discrepancy in activity. However, it was also found that the lactone prodrug used in the context of the doubly reduced peptide isostere, i.e. 3, was chemically unstable at physiological pH. Rapid cyclization to the diketopiperazine 5 significantly reduced FTase inhibitory activity.40 Simple N-alkylation of the reactive secondary amine to give 4 led to loss of activity vs. FTase. To simultaneously protect the compound from both metabolic inactivation (via peptidases) and chemical instability, isosteric replacements of the second amide bond other than methylene-amino were explored. Since the second amide bond in the tetrapeptide inhibitors could be reduced without loss of activity in vitro, peptide bond replacements which were both rigid (olefin) and flexible (alkyl, ether) were synthesized. 

The is-olefin was prepared as a trans-amide bond replacement. A number of compounds incorporating substituents to mimic both natural and unnatural amino acid sidechains were prepared by adapting chemistry developed by Ibuka for the synthesis of Zs-olefin peptide isosteres (see Scheme l).40,41 The key step involved anti-SN2 displacement of vinyl mesylate 8 by boron trifluoride-activated cuprate addition. Compounds containing butyl, propyl, and benzyl substituents at the allylic positions to mimic the aj and sidechains produced potent FTase inhibitors (Table 4). 

The methyleneoxy peptide isostere was also used to replace the aj-aj amide bond. The requisite ether isostere dipeptides were synthesized according to Scheme 2.42 High levels of 1,4-asymmetric induction were observed in the alkylation of morpholinone 14 pseudo-allylic A, 3 strain in acylmorpholinone 14 caused the... 

For many of the prominent inhibitor families (Fig. 3.6.1, Boxes 12 and 13), the available synthetic strategies do not fulfil these requirements. In the synthesis of peptide aldehydes, e.g., the parallel synthesis of variable structures without race-mization is an unsolved problem. The same applies to the synthesis of many peptide isosteres such as the norstatines or the l,3-diamino-2-propanols. Typically, combinatorial variation of the N-terminal and C-terminal positions can be easily attained. The side chain of the isosteric building block itself and its stereochemistry can, however, currently be varied only by a synthetic effort this excludes versatile variation of the central inhibitory element. 

Members of a second prominent group of mechanism-based inhibitors contain a peptide isostere, an element mimicking an intermediate formed during amide bond cleavage. Inhibitors of metalloproteases often contain a metal-chelating unit such as hydroxamate or phosphonic acids, which act as a bidentate ligand. 

Peptide isostere Transition state Aspartate-, serine-... 

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