title: Benzhydrylamine linker grafting: a strategy for the improved synthesis of C-terminal peptide amides.
abstract: The standard p-MBHA resin used during Boc-chemistry synthesis of peptides carrying C-terminal carboxamides is compromised by batch-to-batch variations in its performance. This can cause artificially 'difficult' couplings during peptide chain assembly, which may ultimately lead to failed syntheses given the inability to achieve acceptable coupling yields. To overcome these problems, we have developed a new approach by grafting a functionalized benzhydrylamine linker onto well-characterized and well-performing PAM resins. We combine optimized Boc-chemistry, high-performing PAM resins and new benzhydrylamine-based linkers to achieve improved syntheses of peptide amides. Here we present the synthesis of two new benzhydrylamine linkers and their attachment to selected PAM resins. This novel solid support was evaluated through the synthesis of selected 'difficult' conotoxins and monitoring the coupling efficiency using quantitative ninhydrin assay. The results show a superior performance of the novel linker solid support compared to the standard p-MBHA resins routinely used. In summary, we describe an alternative linker-resin system that allows improved access to C-terminal amide peptides employing Boc/Bzl chemistry.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia.
authors.forename: Dianne
authors.initials: D
authors.lastname: Alewood
authors.forename: Gene
authors.initials: G
authors.lastname: Hopping
authors.forename: Andreas
authors.initials: A
authors.lastname: Brust
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D001559:Benzhydryl Compounds / Q000737:chemistry*; D020916:Conotoxins / Q000138:chemical synthesis / Q000737:chemistry; D005563:Formic Acid Esters / Q000737:chemistry; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: C030545:4-methylbenzhydrylamine resin; D000577:Amides; D001559:Benzhydryl Compounds; D020916:Conotoxins; D005563:Formic Acid Esters; D010455:Peptides; C000345:t-butyloxycarbonyl group; C004531:benzhydrylamine