Peptides Transformation

Summary 

The sulfonamide moiety is introduced as a potential transitional isostere for hydrolysis of the amide bond.Subsequently, the increased acidity of the sulfonamide N-H compared to the conventional amide N-H was investigated in the development of a peptide sulfonamide synthesis acceptor molecule for binding and catalysis.For instance.The structural units required for these compounds can be obtained by efficient synthesis, which also makes it possible to synthesize oligopeptide sulfonamides and peptidyl sulfonamide-β peptide hybrids.In addiction,The structural consequences of the introduction of peptidyl sulfonamide residues were investigated and further investigated by the synthesis of cyclic peptidyl sulfonamides, for example, by ring closure metathesis.

Introduction

The peptide-amide bond is the central recurring structural element of peptides and proteins.Not only it is virtually the only relatively rigid structural moiety because of the double bond character of the amide bond,but it also plays a crucial role in bio-recognition and bio-interactions because of its ability to form hydrogen bonds. 

However,this stable linkage in between amino acid residues is nevertheless easily cleaved by appropriate proteases. Therefore, replacement of this moiety has been widely exploited for the development of protease inhibitors. Especially interesting with respect to this are replacements of the amide by isosteric groups mimicking both shape and electronic environment of the transition state of its hydrolysis. By virtue of its complementarity with the active site of a protease strong binding and powerful inhibitors can be obtained.

We have introduced the sulfonamide moiety as potential protease transition state isosteres and decided to explore and investigate its synthesis, incorporation into peptides as well as its properties.In this short survey we shall focuss on the replacement of (a) crucial peptide-amide bond(s) by the sulfonamide moiety. Emphasis will be placed on the preparative aspects of the peptidosulfonamides and peptide-peptidosulfonamide hybrids, since in many cases this turned out to be a bottle neck. Where possible structural and/or biological properties will be highlighted. Transformation of a peptide – naturally consisting of αamino acid residues – into a sequence in which each amide is replaced by a sulfonamide moiety would lead to an αpeptidosulfonamide oligomer, which is probably not stable, because α-amino sulfonamides are not stable.

They can undergo a fragmentation reaction leading to expelsion of sulfur dioxide and thereby disappearance of the isosteric group [1, 2]. However, fragmentation can be easily circumvented by having an additional methylene unit between the amino group and the sulfonic acid moiety. In this way β-amino sulfonic acids and the corresponding amides are obtained. The first approach for the synthesis of these β-amino sulfonamides featured the preparation of a sulfinylchloride followed by coupling to an amine originating from an amino acid or peptide – either in solution or on the solid phase  – and subsequent oxidation of the resulting sulfinamide to the sulfonamide [2–7]. The advantage of this approach is that the relatively reactive sulfinylchorides – as compared to sulfonylchlorides – can be used in coupling reactions, the disadvantage is their limited stability.

However, in this way a variety of α- and β-substituted sulfonamides could be prepared also derived from amino acids containing functional groups in their side chains [6]. The sulfinylchloride approach was used for introduction of the sulfonamide as a protease transition state isostere in potential HIV-protease inhibitors, thermolysin and thrombine inhibitors as well as haptens for generation of catalytic antibodies [5]. Unfortunately, all so far with negative results.

References

1.Moree, W. J., Van Gent, L. C. Van Der Marel, G. A. and Liskamp, R. M. J., Synthesis of peptides containing a sulfinamide or a sulfonamide transition state isostere, Tetrahedron 49, (1993) 1133–1150.Google Scholar

2.Sommerfeld, T. and Seebach, D., Synthesis of ψ[SCH 2]-, ψ[SOCH 2]-and ψ[SO2CH2]-peptide isosteres, Angew. Chem. Int. Ed. Engl., 34 (1995) 553–553.Google Scholar

3.Moree, W. J., Van Der Marel, G. A. and Liskamp, R. M. J., Peptides containing a sulfinamide or a sulfonamide moiety: New transition state isosteres, Tetrahedron Lett., 32 (1991) 409–412.Google Scholar

4.Moree, W. J., Van Der Marel, G. A. and Liskamp, R. M. J., Synthesis of Peptides containing the β-substituted aminoenthane sulfinamide or sulfonamide transition-state isostere derived from amino acids, Tetrahedron Lett., 33 (1992) 6389–6392.Google Scholar

5.Moree, W. J., Van Der Marel, G. A. and Liskamp, R. M. J., Synthesis of peptidosulfinamides and peptidosulfonamides containing the sulfinamide or sulfonamide transition-state isostere, J. Org. Chem., 60 (1995) 5157–5169.Google Scholar

6.Löwik, D. W. P. M. and Liskamp, R. M. J., Synthesis of α-and β-substituted aminoethane sulfonamide arginine-glycine mimics, Eur. J. Org. Chem., (2000) 1219–1228.Google Scholar

7.De Bont, D. B. A., Moree, W. J. and Liskamp, R. M. J., Molecular diversity of peptidomimetics: Approaches to the solid phase synthesis of peptidosulfonamides, Bioorg. Med. Chem., 4 (1996) 667–672.

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