Head-to-tail macrocyclization of cysteine-free peptides using an o-aminoanilide linker. Issue 8 (1st May 2018)

• Record Type: Journal Article
• Authors: Ohara, Takumi; Kaneda, Masato; Saito, Tomo; Fujii, Nobutaka; Ohno, Hiroaki; Oishi, Shinya
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 8(2018)
• Page Start: 1283
• Page End: 1286
• Publication Date: 2018-05-01
• Subjects: CXCR4 CXC chemokine receptor 4 -- Dbz 3, 4-diaminobenzoic acid -- DPPA diphenylphosphoryl azide -- Nal 3-(2-naphthyl)-l-alanine -- NCL native chemical ligation -- Pbf 2, 2, 4, 6, 7-pentamethyldihydrobenzofuran-5-sulfonyl -- SDF-1 stromal cell-derived factor 1 -- SPPS solid-phase peptide synthesis; Chemokine -- CXCR4 antagonist -- Cyclic peptide -- Macrocyclization -- Microflow reaction; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.03.027
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A head-to-tail macrocyclization protocol for the preparation of cysteine-free cyclic peptides was investigated. The o -aminoanilide linker constructed in the peptide sequence by a standard Fmoc-based peptide synthesis procedure was subjected to nitrite-mediated activation under acidic conditions toward N -acyl benzotriazole as the active ester species. The subsequent cyclization smoothly proceeded by neutralization in the presence of additives such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) to afford the expected cyclic pentapeptide, a CXCR4 antagonist. The cyclization efficiencies were dependent on the precursor open-chain sequence. The application of this step-wise activation-cyclization protocol to microflow reaction systems is also described.