Peptides containing the sulfonamide junction. 2. Structure and conformation of Z-Tau-Pro-D-Phe-NHiPr

Abstract

The taurine (Tau) containing N‐protected pseudotripeptide isopropylamide Z–Tau–Pro–D‐Phe–NHiPr (1) has been specifically designed and synthesized as suitable model to test the ability of the sulfonamido group to participate as H‐bond acceptor to a type II β‐turn and to get information on the preferred rotameric conformation around the S—N bond and the hybridization state of the nitrogen atom. The present structural investigation reveals that, although the sulfonamide junction is invariably folded in a gauche mode, the β‐turn structure, stabilized by the 4 → 1 hydrogen bond, is not found in the crystal and the sulfonamido oxygen atoms are not involved in any intra‐ or intermolecular hydrogen‐bond interaction. More than one conformer populates the CDCl3 solution with only a minor contribution by the expected β‐turn. The Pro nitrogen is significantly pyramidalized and the nitrogen lone pair points in opposite direction to that of the Pro CαH bond thus adopting R chirality, in an arrangement practically identical to that found in the previously studied homochiral analogue Z–Tau–Pro–Phe–NHiPr. © 2000 John Wiley & Sons, Inc. Biopoly 54: 379–387, 2000

Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals

“…In contrast to the relatively rigid amide peptide bond, the sulfonamide bond is more freely rotatable and the cis-trans isomerism is not observed [127,130]. This greater rotational freedom allows for the sulfonamide oxygens to assume a variety of positions, where one oxygen occupies a cis or trans orientation with respect to the amide N-H, while the other oxygen is in neither a cis nor trans When compared to the amide moiety, the sulfonamide group is a stronger hydrogen bond donor [127] and the sulfonamide N-H is more acidic than the amide N-H, but a weaker hydrogen bond acceptor [127][128][129]. Furthermore, the hydrogen bond accepting character of the sulfonamide moiety is split between two accepting sites due to the two sulfonamide oxygens.…”

“…Consequently, peptides containing sulfonamide substitutions have been investigated as transition state isosteres for the use as protease inhibitors [126]. When compared to the amide moiety, the sulfonamide group is a stronger hydrogen bond donor [127] and the sulfonamide N-H is more acidic than the amide N-H, but a weaker hydrogen bond acceptor [127][128][129]. Furthermore, the hydrogen bond accepting character of the sulfonamide moiety is split between two accepting sites due to the two sulfonamide oxygens.…”

“…The replacement of one or more amide bonds along a peptide backbone with sulfonamides has been successfully applied to develop peptidosulfonamide peptide analogues that display increased stability towards proteases compared to their unmodified analogues while also maintaining satisfactory biological activity [127,128,131]. The most common method of applying this strategy is to identify the preferred protease cleavage sites on a peptide and substitute the amides at those locations with sulfonamides.…”

Synthesis of sulfonopeptides

“…The investigation results revealed that, although the sulfonamide junction was invariably folded in a gauche mode, the β-turn structure was not found in the crystal and the sulfonamido oxygen atoms were not involved in any intra-or intermolecular hydrogen-bond interactions. The Pro nitrogen was significantly pyramidalized and the nitrogen lone pair pointed in the opposite direction to that of the Pro Cα-H bond thus adopting R chirality, in an arrangement practically identical to that found in the previously studied homochiral analogue Z-Tau-Pro-Phe-NH i Pr (Scheme 19) 64. The sulfonamide modified RGD analogs were synthesized from Z-Tyr-OH.…”

Radiopharmaceuticals for PET Imaging - Issue A

“…Consequently, peptides containing sulfonamide substitutions have been investigated as transition state isosteres for the use as protease inhibitors [126]. When compared to the amide moiety, the sulfonamide group is a stronger hydrogen bond donor [127] and the sulfonamide N-H is more acidic than the amide N-H, but a weaker hydrogen bond acceptor [127][128][129]. Furthermore, the hydrogen bond accepting character of the sulfonamide moiety is split between two accepting sites due to the two sulfonamide oxygens.…”