Optimization of Solid-Phase Synthesis of [Ala8]-dynorphin A

Núria A. Solé, George Barany

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211 Scopus citations

Abstract

[Ala8]-dynorphin A, a potent k-selective opioid heptadecapeptide with numerous sensitive side-chain residues, has been prepared by solid-phase synthesis using base-labile Nα-9-fluorenylmethyloxycarbonyl (Fmoc) protection and side-chain anchoring to a tris(alkoxy)benzylamide “PAL”-resin. Final cleavage and deprotection was carried out with reagent R, trifluoroacetic acid-thioanisole-1,2-ethanedithiol-anisole (90:5:3:2), reagent K, trifluoroacetic acid-phenol-water-thioanisole-1,2-ethanedithiol (82.5:5:5:5:2.5), and reagent B, trifluoroacetic acid-phenolwater-triisopropylsilane (88:5:5:2); optimal reaction and workup conditions are described. Crude peptide products were evaluated by analytical high-performance liquid chromatography (HPLC), capillary zone electrophoresis (CZE), ánd direct fast atom bombardment and ion electrospray mass spectrometry (FABMS and ESMS). Tryptophan alkylation side reactions involving a 2,4,6-trimethoxybenzyl (Tmob) group from asparagine or 2,2,5,7,8-pentamethylchroman-6-ylsulfonyl (Pmc) groups from arginines occur under insufficiently long cleavage times and/or when certain scavenger components are omitted from the cleavage cocktails, but can be minimized under the best conditions. Conditions with reagent B, 1 h, 25 °C, and extractive workup, were followed up preparatively to provide [Ala8]-dynorphin A in excellent purity (>99%) and 58% overall isolated yield based on the C-terminal aminó acid anchored on the resin.

Original languageEnglish (US)
Pages (from-to)5399-5403
Number of pages5
JournalJournal of Organic Chemistry
Volume57
Issue number20
DOIs
StatePublished - Sep 1 1992

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