Synthesis of [1‐8‐NαC]‐zanriorb A1, alanine‐containing analogues, and their cytotoxic and anti‐inflammatory activity

Abstract

The synthesis of the orbitide[1-8-NαC]-zanriorb A1, isolated from the medicinal plant Zanthoxylum riedelianum, was investigated by solution-phase macrocyclization of a linear peptide and on-resin solid-phase macrocyclization with an acylsulfonamide safety-catch linker. The solution-phase route produced a mixture of proline rotamers, and the main component was assigned as the trans, cis rotamer, identical to the natural product. The on-resin cyclization was less successful, producing mainly a linear peptide, and minor cyclic products as rotameric mixtures. Although the natural product was reported to be significantly cytotoxic against Jurkat leukemia T cells, our synthetic peptides were inactive, suggesting the presence of other rotamers or impurities in the naturally isolated material. Additional analogues of zanriorb A1 were synthesized in which proline and glycine residues were replaced with alanine. While these analogues were not cytotoxic, several of them inhibited the production of nitric oxide in lipopolysaccharide (LPS)-stimulated macrophages. The most active compound, cyclic [Ala 5,6,8 ]-zanriorb A1 had an IC 50 of 22 μM and was more potent compared with the standard NG-monomethyl-L-arginine acetate (L-NMMA) with an IC 50 of 98 μM, indicating their strong anti-inflammatory potential.

One-Step Synthesis of 3-(Fmoc-amino acid)-3,4-diaminobenzoic Acids

“…Despite the critical role of C-terminal functionalities in peptide chemistry, their preparation remains challenging due to the nature of C- to N-terminal preparation via conventional solid-phase peptide synthesis (SPPS) . The use of a safety-catch resin is a feasible strategy for this purpose; in this approach, a given moiety is introduced in the cleavage step to the C-terminus of the product . Diaminobenzoate (Dbz) resin is an efficient safety-catch resin that is widely used to prepare thioesters. , Dbz resin was also used in the C-terminal functionalization of other peptides, including thiolactones, acylbenzimidazolinones, and cyclic peptides .…”

“… 2 The use of a safety-catch resin is a feasible strategy for this purpose; in this approach, a given moiety is introduced in the cleavage step to the C-terminus of the product. 3 Diaminobenzoate (Dbz) resin is an efficient safety-catch resin that is widely used to prepare thioesters. 4 , 5 Dbz resin was also used in the C-terminal functionalization of other peptides, including thiolactones, 6 acylbenzimidazolinones, 7 and cyclic peptides.…”