Lactone and Lactam Library Synthesis by Silver Ion-Assisted Orthogonal Cyclization of Unprotected Peptides

Abstract

An orthogonal cyclization strategy has been developed to prepare cyclic peptides individually or as a mixture in aqueous solutions. In this strategy, we propose a dual activation by entropy and enthalpy through Ag + ion coordination of the reactive ends of an unprotected peptide thioester to permit long-range acyl migration. As a result, both lactamization and lactonization of linear peptides can be realized simultaneously or selectively by controlling the reaction conditions. At pH 4, lactonization is favored due to the strong protonation of the amino moieties. However, at pH 5-5.7 lactamization of R-amine of the N-terminal amino acid is favored, particularly with DMSO as a cosolvent. At pH > 6, lactamization of the -amine of lysine becomes significant. Furthermore, the Ag + ion complexation with the peptide thioester precursor in aqueous buffered solutions may facilitate entropy-favored ring-chain tautomerization, which in turn promotes formation of monomeric cyclic products and thereby reduces unwanted oligomerization. Evidence supporting Ag + ion-directed ringchain tautomerization includes product distribution profiles, the concentration-independent nature of the cyclization, and lack of competition by intermolecular coupling with other unprotected peptide segments. The N-terminal amino acid has been found to exert a profound effect in conferring high specificity toward endto-end cyclization. Examination of 23 linear peptide precursors containing different N R -amino acids showed that the probability of lactamization is almost 20-fold greater in R-amines than -amines with N-terminal Gly, Asn, Asp, and Ser. Unprotected linear peptides ranging from 5 to 16 amino acid residues were cyclized individually or as a mixture with good to excellent yields. More importantly, this strategy paves the way for a new approach to synthesizing cyclic peptide libraries in which unprotected peptides are cyclized and released from the resin at the same time. The obtained libraries can, therefore, be used directly for bioassays without further chemical manipulations. This method is also useful for the synthesis of bicyclic peptides containing both sulfur-sulfur and lactam linkages.

Correlations of Cationic Charges with Salt Sensitivity and Microbial Specificity of Cystine-stabilized β-Strand Antimicrobial Peptides

“…Peptide Synthesis and Purification-All peptides were synthesized by a stepwise solid phase peptide synthesis (24) performed manually or on an ABI 431A synthesizer using t-butyloxycarbonyl chemistry on a thioester resin (25,26). The peptides cleaved from the resin by HF and purified by preparative RP-HPLC have been reported previously (18,20).…”

The cyclization of peptides and depsipeptides

“…Both examples rely on the availability of Cys residues in the peptide. Attempts to overcome this necessity have included coordination of the Nterminal end of a peptide with C-terminal thioesters using Ag + ion coordination [59] and Kent et al's [60] formation of a transient thiolactone link which includes an auxiliary group which is removed, leaving a Gly residue as summarized in Scheme 9.…”

Amphiphilic Homochiral Oligopeptides Generated via Phase Separation of Nonracemic α‐Amino Acid Derivatives and Lattice‐Controlled Polycondensation in a Phospholipid Environment

“…The experiments were performed with monomers with perdeuterated stearyl chains that yielded a difference between the enantiomers [12] [21] of 35 and 37 mass units, respectively. The polycondensation reactions, performed at 20 or 48, were initiated by injection of aqueous solutions containing AgNO 3 [23] or I 2 /KI [24]. The reaction time was set to 2 h. The oligopeptides were collected from the H 2 O surface, and their diastereoisomeric distribution was determined by MALDI-TOF-MS. No measurable isotope effects were observed on interchanging the deuterium labeling of the two enantiomers or the enantiomeric excess in the nonracemic mixtures of monomers.…”