title: Review backbone N-modified peptides: How to meet the challenge of secondary amine acylation.
abstract: Backbone N-substitution of peptides (N-Me and N-alkyl) has become of special interest as a chemical tool for peptide lead modification, either to improve biological activity or to optimize key pharmacokinetic characteristics. For the synthesis of backbone N-methylated peptides, many protocols have been developed already, yet some effort often has to be made to find appropriate conditions for the acylation of N-Me residues. Fewer examples are reported of peptides with other backbone N-substituents different than N-Me, and their synthesis is frequently reported as difficult. The synthesis of such peptides becomes more difficult as the size of the N-substituent increases. Coupling methods that work for the synthesis of N-methylated peptides were often found to fail when applied to peptides with larger N-substituents. This review addresses the challenges of the synthesis of backbone N-modified peptides, focusing on N-substituents larger than the N-Me group.
authors.affiliation: Institute for Research in Biomedicine, Deparment of Chemistry and Molecular Pharmacology, Barcelona Science Park, Baldiri Reixac 10, Barcelona, 08028, Spain.|CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, Barcelona, 08028, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Fernández-Llamazares
authors.affiliation: Institute for Research in Biomedicine, Deparment of Chemistry and Molecular Pharmacology, Barcelona Science Park, Baldiri Reixac 10, Barcelona, 08028, Spain.|CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, Barcelona, 08028, Spain.
authors.forename: Jan
authors.initials: J
authors.lastname: Spengler
authors.affiliation: Institute for Research in Biomedicine, Deparment of Chemistry and Molecular Pharmacology, Barcelona Science Park, Baldiri Reixac 10, Barcelona, 08028, Spain.|CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, Barcelona, 08028, Spain.|Department of Organic Chemistry, University of Barcelona, Martí i Franquès 1-11, Barcelona, 08028, Spain.|School of Chemistry and Physics, University of KwaZulu-Natal, 4001 Durban, South Africa.|School of Life Sciences, Department of Chemistry, Yachay Tech, Yachay City of Knowledge, Urcuquι 100119, Ecuador.|Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia.
authors.forename: Fernando
authors.initials: F
authors.lastname: Albericio
mesh_terms: D000215:Acylation; D000588:Amines / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*
chemical_list: D000588:Amines; D010455:Peptides
keywords: acylation; coupling reagent; methylation