Azasulfonamidopeptides as peptide bond hydrolysis transition state analogues. Part 1. Synthetic approaches

Abstract

The title compounds, a novel class of peptide analogues in which an a-amino acid residue is replaced by a hydrazine-1.2-diyl sulfonyl group -NHNRSO,-, are of potential interest as proteinase inhibitors. Synthetic approaches to such compounds and the X-ray molecular structures of two examples (1 6 and 28) are reported.

crystal structure analyses of azasulfuryltripeptides reveal potential for γ‐turn mimicry†

“…X‐ray crystallographic analyses have been previously reported only for azasulfuryldipeptides: N ‐(Ac)‐AsF‐Gly‐OMe ( 19 ) and N ‐(Boc)‐AsF‐Pro‐OMe ( 20 ) . In comparing the X‐ray structures of the azasulfuryltripeptides 10 and 11 with dipeptides 19 and 20 , the ω dihedral angles for the former were respectively 72.5° and −55.5°, consistent with the preferred staggered conformation (±60°) found in X–ray analyses of sulfonamides; however, those of the latter were −90°, and closer to the eclipsed conformation (±100°) of sulfonamides.…”

“…Azasulfurylpeptides 1 possess an amino acid residue from which the C α H and carbonyl have been respectively replaced by nitrogen and a sulfonyl group (Figure ) . Although few examples of these peptidomimetics have been reported, their potential to mimic the tetrahedral geometry during amide bond hydrolysis was exploited by the insertion of azasulfurylphenylalanine (AsF) into a transition‐state mimic, micromolar inhibitor of the human immunodeficiency virus‐1 (HIV–1) proteinase, azasulfurylpeptide 2 (Figure ) .…”

“…In the first reported syntheses of azasulfurylpeptides, amine, and hydrazide building blocks 3 and 4 were combined with sulfuryl chloride using a catalytic amount of antimony pentachloride (SbCl 5 ); however, symmetric sulfamide 6 was often formed as side product . N –Benzyl protected hydrazide precursors 4b could be employed to introduce a side‐chain onto the N –aminosulfamide residue (Scheme ) …”

Azasulfurylpeptide Modulation of CD36-Mediated Inflammation Without Effect on Neovascularization

“…Azasulfurylpeptides (e.g., 3 – 6 , Figure 1) are peptides containing an N -aminosulfamide as amino amide surrogate [20,21,22,23,24,25]. Combining semicarbazide [26] and sulfonamide properties [27,28], N -aminosulfamides were shown (by X-ray crystallography) to restrict model peptide backbones to geometry characteristic of the central residues in ideal β- and γ-turns [22].…”

Solid-Phase Synthesis of Azasulfurylphenylalanine4-GHRP-6

“…Azasulfurylpeptides possess an amino sulfamide as an amino amide surrogate in which the CH and carbonyl components are respectively replaced by nitrogen and a sulfonyl group [1][2][3][4]. Uniting the properties of azapeptides [5] and sulfonamides [6][7], azasulfurylpeptides have served as transition state mimics of amide bond hydrolysis in a micromolar human immunodeficiency virus-1 (HIV-1) proteinase inhibitor [2].…”