A Unified Approach to Access N‐Acyl Sulfonamide Tethered Peptide Conjugates

Abstract

Herein we demonstrate a chemoselective reaction of Nβ‐protected amino alkyl sulfonyl azides with in situ generated Nα‐protected amino acid selenocarboxylates via step wise intramolecular cyclization followed by decomposition to obtain N‐acyl sulfonamide tethered peptidyl conjugates. The protocol offers the synthesis of orthogonally protected N‐acyl sulfonamide tethered peptidomimetics under simple and mild reaction conditions employing commercially available amino acids in presence of NaBH2Se3 as a selenating agent. Also, the synthesis of N‐acyl sulfonamide tethered amino acid and aryl conjugates were accomplished as an extension of the above strategy.

Synthesis and human carbonic anhydrase I, II, VA, and XII inhibition with novel amino acid–sulphonamide conjugates

“…Most of the compounds exhibited inhibition constants K I values ranging from 0.5 to 8.9 nM against hCA II, being more effective inhibitors than the standard sulphonamide acteazolamide AZA. In parallel to the results in hCA I, 4-(2-aminoethyl)benzenesulphonamide derivatives (1-12) showed better inhibition than the corresponding homosulphonamide derivatives (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Compounds 1 and 3 also showed a better inhibition against hCA VA compared to AAZ, while compounds 2, 4-6 showed a comparable inhibition to that of AAZ.…”

“…Due to their antimicrobial and CA inhibitory properties, both primary and secondary sulphonamide derivatives are under investigation to determine compounds possessing the highest activity with possibly few side-effects 19,20 . For this reason, many studies on sulphonamide derivatives have been done in recent years 3,8,9,12,18,21 . Moreover, our group previously observed the CA inhibitory properties of some primary sulphonamide derivatives incorporating dipeptide and amino acid moieties, which inhibited some pharmacologically relevant CA isoforms at nanomolar levels [16][17][18] .…”

Ferric Chloride-Mediated Transacylation of N-Acylsulfonamides

“…The N -acylsulfonamide group is of great utility in organic synthesis and medicinal chemistry. , This group is well-known as the Kenner safety-catch linker because the secondary N -acylsulfonamide group is stable to nucleophilic reagents, anhydrous acids, and aqueous alkali but becomes susceptible to nucleophilic attacks after N -alkylation, making the linker useful for solid-phase peptide synthesis. − This group has also been used as a synthetic building block for preparing bioactive pharmaceutical agents and as a chemoselective acylating agent for amines and amino alcohols . Its inertness to chemical and enzymatic hydrolysis, together with its adequate acidity, makes it an ideal bioisostere of the carboxylic acid group with important pharmacological applications. ,− …”