Tri‐Orthogonal Scaffolds for the Solid‐Phase Synthesis of Peptides

• Published in: European journal of organic chemistry Vol. 2018; no. 37; pp. 5180 - 5192
• Main Authors: Pícha, Jan, Fabre, Benjamin, Buděšínský, Miloš, Hajduch, Jan, Abdellaoui, Mehdi, Jiráček, Jiří
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 09.10.2018; Wiley Subscription Services, Inc
• Subjects: Alkynes; Amino acids; Chemical synthesis; Chemistry; Chemistry, Organic; Click chemistry; Organic chemistry; Peptide synthesis; Peptides; Physical Sciences; Proteins; Scaffolds; Science & Technology; Solid phase synthesis; Tips; AMINO-ACID; AFFINITY; TRIFUNCTIONAL SCAFFOLD; DRUG DISCOVERY; Peptide synthesis; Click chemistry; DEPROTECTION; Solid-phase synthesis; Scaffolds; MOLECULES
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201800601

Multi‐orthogonal scaffolds can be useful for the attachment of several different compounds to the same central skeleton. Such compounds can find applications in the development of protein mimics because of their potential to mimic several distant epitopes in the protein structure. Three new tri‐orthogonal variants of a previously reported scaffold have been developed that are suitable for the solid‐phase synthesis of three different peptides on the same skeleton. Different chemical moieties were combined for the phased attachment of amino acids to the scaffolds: Fmoc‐ or Alloc‐protected amine, free or TIPS‐protected alkyne or azido group. Several model compounds were prepared, characterized, and compared for their suitability as new scaffolds for peptide synthesis. All three scaffolds provided peptides with satisfactory yields and purities, making them suitable for a synthesis of libraries of compounds. Three tripodal scaffolds were developed and tested for the step‐by‐step synthesis of three different peptides on the same scaffold by solid‐phase synthesis. Such compounds with three different peptides attached to a central core could mimic large proteins and find applications in modulating protein–protein interactions.