Solid phase synthesis of cyclic peptides: model studies involving i− ( i +4) side chain‐to‐side chain cyclisation

Abstract

Conditions for the synthesis of i-(i + 4) side chain-to-side chain head-to-tail Lys-->Glu and Glu-->Lys linked cyclic peptides related to hypoglycaemic analogues of human growth hormone hGH [6-13] have been examined. The success of the cyclisation reaction with the corresponding resin-bound, partially protected linear peptides was found to be both reagent as well as sequence dependent, with competing inter-chain oligomerisation predominating in some cases. The results also indicated that protection with the bulky Fmoc group of the amino acid residues immediately adjacent to the side chain-deprotected Lys and Glu residues, which participate in the cyclisation reaction, enhanced the rate of lactam formation.

The synthesis and study of side‐chain lactam‐bridged peptides

“…However, monocyclic analogs of human calcitonin in which the side chains of aspartic acid and lysine residues in positions 17 and 21 were linked to form a 20‐atom macrocycle have consistently given much lower yields 33, 34. Similar effects of the sequence context have been reported by Hearn and co‐workers 35. These authors have also reported that the presence of an Fmoc‐protected amino acid residue immediately N‐terminal to the residues being cyclized improved the cyclization result, presumably by limiting the conformational freedom of the peptide chain during the reaction.…”

The cyclization of peptides and depsipeptides

“…After specific deprotection of the Lys and Glu side chains, conventional strategies can then be used to form the amide bond between the side chains. Model studies [54] on utilizing an on-resin (4-methylbenzhydryl resin) cyclization of Fmoc-Lys-Phe-D-Ala-Pro-Glu-Gly (Peptide 1) and its analogue (Peptide 2) with the positions of Lys and Glu reversed, provided the results shown in Table 2. DIC over extended times proved to be the best conditions, with peptide 1 being lactamized easier than peptide 2.…”

Peptides Constrained by an Aliphatic Linkage between Two CαSites: Design, Synthesis, and Unexpected Conformational Properties of ani,(i+4)-Linked Peptide

“…In general, peptides and peptidomimetics may be constrained to adopt a stable β-turn conformation by the formation of linkages between the i and i + 3 positions, whereas incorporation of linkages between the i and i + 4 positions leads to stable α-helical structures . There are a very few examples of i and i + 4 lactam-bridged peptides in which turn structures appear to be preferentially stabilized; of particular note is a recent study of human calcitonin analogues in which a type-I β-turn is observed by CD . This may indicate that the stabilization of helical conformation by bridging two residues is more context-dependent than previously thought.…”