Using cyclic peptide mixtures as probes for metal ion host-guest interactions

Chen, Jian J.; Teesch, Lynn M.; Spatola, Arno F.

doi:10.1007/bf00131081

Cited by 8 publications

(7 citation statements)

References 14 publications

(10 reference statements)

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“…[1][2][3][4][5] Focusing on the Fmoc/tBu methodology, a number of amino acids have proven suitable for side-chain anchoring strategies. Most frequently, this has been accomplished through a side-chain carboxyl function of Asp or Glu, which provides access to peptides that contain Asx or Glx, [2][3][4][5][11][12][13][14][15][16] depending on the handle used.…”

Section: Introductionmentioning

confidence: 99%

Side‐chain anchoring strategy for solid‐phase synthesis of peptide acids with C‐terminal cysteine

et al. 2003

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Many naturally occurring peptide acids, e.g., somatostatins, conotoxins, and defensins, contain a cysteine residue at the C-terminus. Furthermore, installation of C-terminal cysteine onto epitopic peptide sequences as a preliminary to conjugating such structures to carrier proteins is a valuable tactic for antibody preparation. Anchoring of N(alpha)-Fmoc, S-protected C-terminal cysteine as an ester onto the support for solid-phase peptide synthesis is known to sometimes occur in low yields, has attendant risks of racemization, and may also result in conversion to a C-terminal 3-(1-piperidinyl)alanine residue as the peptide chain grows by Fmoc chemistry. These problems are documented for several current strategies, but can be circumvented by the title anchoring strategy, which features the following: (a). conversion of the eventual C-terminal cysteine residue, with Fmoc for N(alpha)-amino protection and tert-butyl for C(alpha)-carboxyl protection, to a corresponding S-xanthenyl ((2)XAL(4)) preformed handle derivative; and (b). attachment of the resultant preformed handle to amino-containing supports. This approach uses key intermediates that are similar to previously reported Fmoc-XAL handles, and builds on earlier experience with Xan and related protection for cysteine. Implementation of this strategy is documented here with syntheses of three small model peptides, as well as the tetradecapeptide somatostatin. Anchoring occurs without racemization, and the absence of 3-(1-piperidinyl)alanine formation is inferred by retention of chains on the support throughout the cycles of Fmoc chemistry. Fully deprotected peptides, including free sulfhydryl peptides, are released from the support in excellent yield by using cocktails containing a high concentration (i.e., 80-90%) of TFA plus appropriate thiols or silanes as scavengers. High-yield release of partially protected peptides is achieved by treatment with cocktails containing a low concentration (i.e., 1-5%) of TFA. In peptides with two cysteine residues, the corresponding intramolecular disulfide-bridged peptide is obtained by either (a). oxidation, in solution, of the dithiol product released by acid; (b). simultaneous acidolytic cleavage and disulfide formation, achieved by addition of the mild oxidant DMSO to the cleavage cocktail; or (c). concomitant cleavage/cooxidation (involving a downstream S-Xan protected cysteine), using reagents such as iodine or thallium tris(trifluoroacetate) in acetic acid.

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Section: Introductionmentioning

confidence: 99%

Side‐chain anchoring strategy for solid‐phase synthesis of peptide acids with C‐terminal cysteine

et al. 2003

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“…The product (11) was crystallized from ethyl acetate/hexane, filtered, washed with hexane, and dried in vacuo. Yield Anchorage of (11) to hydroxymethyl resin (12) The protocol for attachment of (11) to hydroxymethyl resin is identical to the synthesis of the resin (10). Substitution yield 0.53 mmol/g.…”

Section: N α -(T-butyloxycarbonyl)-γ -(Benzylester)-l-glutamic Acid-βmentioning

confidence: 99%

“…In subsequent reports, we have studied the racemization problem of a C-terminal aspartic acid residue during the synthesis [10] and explored library variations in structure and ring size [11]. More recently, we have reported our studies on metal binding affinities of cyclic peptide mixtures [12] and on the synthesis and characterization of cyclic pseudopeptides containing the ψ[CH 2 NH] surrogate [13]. In this report, we extend our study to cyclic pseudopeptide libraries containing the ψ[CH 2 S] and ψ[CH 2 SO] surrogates.…”

Section: Introductionmentioning

confidence: 99%

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Crozet

Wen

Loo

et al. 1998

Molecular Diversity

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We describe the first examples of a series of cyclic pseudopeptide libraries that have been prepared in a systematic approach in order to facilitate both synthesis and subsequent deconvolution attempts. Our synthetic strategy involved the attachment of a trifunctional amino acid (Asp, Asn or Glu) to a polystyrene resin via its side chain, and stepwise chain elongation using either protected amino acids or a pseudodipeptide building block. Head to tail cyclic peptides were formed by removal of the temporary N- and C-terminal protecting groups followed by ring closure by amide formation. Cyclization of the hexa, hepta, and octapseudopeptides on the resin avoided dimer formation, as monitored by mass spectrometry. We utilized a 'psi-scan' approach in which a second fixed position was serially addressed by stepping a dipeptide surrogate, Pro psi [CH2S]Gly around the rings to generate a group of cyclic pseudopeptide sub-libraries. Oxidation of psi [CH2S] to psi [CH2SO] helped validate the synthesis and also provides a strategy for forming a new set of pseudopeptide libraries (previously described as 'libraries from libraries'). Our results suggest that libraries of cyclic pseudopeptides are an efficient method of preparing and assaying these synthetically more challenging entities as potential drug leads.

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“…A theoretical study on the interaction of metal ions with cyclo[(1R,3S)-c-Acc-Gly] 3 hexapeptide shows its high affinity toward metal ions [35]. Several other studies have also considered the metal cation binding properties of cyclic peptides [36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Metal ion binding of s-block cations and nanotubular cyclic (proline)4: A theoretical study

Chermahini

Dabbagh

et al. 2014

Struct Chem

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The binding interaction of alkali metal ions within the cavity of nanotubular cyclic (proline) 4 [Cyclo(Pro) 4 ] has been studied using quantum chemical density functional theory. The Cyclo(Pro) 4 and its alkali metal ionic complexes were optimized at B3LYP/6-31?G(d) and CAM-B3LYP/6-31?G(d) levels of theory. For each alkali metal ion, two binding modes of complexation with Cyclo(Pro) 4 were considered: tetradentate series of (a) and bidentate series of (b). The binding energies and various thermodynamic parameters of free Cyclo(Pro) 4 and its alkali metal ion complexes were determined. In series of (a), the binding energy of Cyclo(Pro) 4 toward metal ions increases as Li ? [ K ? [ Na ? [ Rb ? . In series of (b), the binding energy order is obtained as Li ? [ Na ? [ K ? [ Rb ? [ Cs ? . The optimized structures are used to perform natural bond orbital analysis. The results indicate that the electron-donating oxygen offers lone pair electrons to the LP* orbitals of metal cations except in the tetradentate Li ? and Na ? complexes, where the electron-donating nitrogen offers lone pair electrons to the LP* orbitals of metal cations. The strength and nature of interactions between alkali metal ions and macrocyclic Cyclo(Pro) 4 was studied using topological parameters at bond critical points (BCP) by AIM analysis. Consequently, these interactions were closed-shell interactions due to their positive r 2 q(r) values at corresponding BCP. The bulk solution effect on the binding interaction between alkali metal ions and Cyclo(Pro) 4 was evaluated using PCM-SCRF optimization calculations at the same level of theory. The obtained optimized geometries and binding energies of gas and solution phases were compared. In addition, the bulk solution effect reduced the binding energies of Cyclo(Pro) 4 ÁÁÁM ? complexes.Keywords Cyclo(Pro) 4 Á Nanotubular cyclic peptide Á AIM analysis Á Solvent effect Á Alkali metal cations Á Hostguest complex Electronic supplementary material The online version of this article (

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Using cyclic peptide mixtures as probes for metal ion host-guest interactions

Cited by 8 publications

References 14 publications

Side‐chain anchoring strategy for solid‐phase synthesis of peptide acids with C‐terminal cysteine

Side‐chain anchoring strategy for solid‐phase synthesis of peptide acids with C‐terminal cysteine

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Metal ion binding of s-block cations and nanotubular cyclic (proline)4: A theoretical study

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