Azasulfonamidopeptides as peptide bond hydrolysis transition state analogues. Part 2. Potential HIV-1 proteinase inhibitor

Abstract

The synthesis of [Nbenzyl-N-(Nubenzyloxycarbonyl-L-asparaginyl) hydrazino]sulfonyl-L-prolyl-Lisoleucyl-L-valine methyl ester 4, a potential HIV-1 proteinase inhibitor, is described.We recently defined feasible synthetic approaches to azasulfonamidopeptides 1, ' which are a novel class of analogues for Boc-Asn(Trt)-OHL Boc-Asn(Trt)-OMe

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

“…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 ) . Although their physical characterization has been limited, azasulfurylpeptides may likely combine properties of azapeptides and sulfonamides, , including (1) lone pair‐lone pair repulsion between adjacent nitrogen favoring a ϕ ‐torsion angle of ±90°, (2) ω ‐torsion angle geometry favored at ±60° and ±100°, respectively for the staggered and eclipsed conformations, (3) enhanced flexibility due to a lower SN rotational barrier, and (4) a tetrahedral geometry about the sulfonyl group with SN and SO bond lengths that are relatively longer than amide bond lengths .…”

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].…”

“…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]. Azasulfurylpeptides may similarly stabilize -turn conformations [8].…”

Transition state isosteres of the γ‐glutamyl peptide bond hydrolysis: synthesis and characterization of the ψ[CH2NH] pseudopeptide analogue of glutathione

“…Both these amide bond surrogates present stability towards enzymatic hydrolysis and maintain a planar structure at the key site; therefore, the sp 3 aminomethylene CH 2 NH group was of interest to mimic the tetrahedral intermediate of γ -Glu-Cys peptide bond hydrolysis [23]. In fact, among the transition state analogues (TSAs) of the cleavable peptide bonds [24][25][26][27][28][29], the ψ[CH 2 NH] isosteric replacement introduces unique properties within the peptide sequence other than the expected enzyme resistance and increased flexibility, i.e. a new base, a new ionizable site and increased H-bond donor ability.…”