One-Pot Peptide Ligation-Oxidative Cyclization Protocol for the Preparation of Short-/Medium-Size Disulfide Cyclopeptides.

Native chemical ligation (NCL) employing the N-methylbenzimidazolinone (MeNbz) linker readily provided the linear precursor of a 16-mer peptide that is difficult to obtain by stepwise solid-phase peptide synthesis. NCL and the workup conditions were improved toward a protocol that allows for quantitative removal of the 4-hydroxymercaptophenol additive and subsequent formation of the disulfide bridge in the NCL cocktail by oxidation in air, tolerated by the presence of tris(hydroxypropyl)phosphine.

The synthesis of an EDTA-like chelating peptidomimetic building block suitable for solid-phase peptide synthesis.

A novo trifunctional EDTA-like peptidomimetic amino acid is described. This unique building block, which is prepared in a straightforward manner from commercialized starting materials, contains three moieties: a hexadentate chelating unit similar to that present in EDTA, and amino and carboxylic groups, which facilitate its introduction into the backbone of peptides using conventional SPPS. As a proof of concept, this building block is introduced into a cyclic peptide inspired from the family of Gratisin analogues.

Review backbone N-modified peptides: How to meet the challenge of secondary amine acylation.

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.

Tackling lipophilicity of peptide drugs: replacement of the backbone N-methyl group of cilengitide by N-oligoethylene glycol (N-OEG) chains.

Cilengitide is an RGD-peptide of sequence cyclo[RGDfNMeV] that was was developed as a highly active and selective ligand for the αvβ3 and αvβ5 integrin receptors. We describe the synthesis of three analogues of this peptide in which the N-Me group has been replaced by N-oligoethylene glycol (N-OEG) chains of increasing size: namely N-OEG2, N-OEG11, and N-OEG23, which are respectively composed of 2, 11, and 23 ethylene oxide monomer units. The different N-OEG cyclopeptides and the original peptide were compared with respect to lipophilicity and biological activity.

The backbone N-(4-azidobutyl) linker for the preparation of peptide chimera.

A robust synthetic strategy for the introduction of the N-(4-azidobutyl) linker into peptides using standard SPPS techniques is described. Based on the example of Cilengitide it is shown that the N-(4-azidobutyl) group exerts similar conformational restraints as a backbone N-Me group and allows conjugation of a desired molecule either via click chemistry or-after azide reduction-via acylation or reductive alkylation.

The first total synthesis of the cyclodepsipeptide pipecolidepsin A.

Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa. This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered γ-branched β-hydroxy-α-amino acid D-allo-(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4-dimethylglutamine, (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D-allo-Thr and L-pipecolic acid.

N-Triethylene glycol (N-TEG) as a surrogate for the N-methyl group: application to Sansalvamide A peptide analogs.

Here we studied the N-triethylene glycol (N-TEG) group as a surrogate for the N-Me group in Sansalvamide A peptide. The five N-TEG and N-Me analogs of this cyclic pentapeptide were synthesized, and their biological activity, lipophilicity and conformational features were compared.

Use of an internal reference for the quantitative HPLC-UV analysis of solid-phase reactions: a case study of 2-chlorotrityl chloride resin.

Here we evaluated the use of internal reference compounds for the rapid assessment of reactions performed in solid-phase. An internal reference compound (commercially available) was bound to the resin, together with the substrate, and cleaved with the products after completion of the reaction. The peak area of the reference compound in the HPLC-UV chromatograms can be correlated directly with those of other compounds present in the reaction mixture, thereby allowing a quantitative interpretation of the chromatograms with respect to conversion and yield.

Rapid and high-yielding cysteine labelling of peptides with N-succinimidyl 4-[18F]fluorobenzoate.

Fast cysteine labelling of peptides promoted by an adjacent arginine has been observed with a standard labelling agent specific for amines, N-succinimidyl 4-[(18)F]fluorobenzoate.

Total regioselective control of tartaric acid.

An efficient strategy to synthesize tartaric acid building blocks for totally regioselective transformations or derivatizations was disclosed. Starting from l-tartaric acid or l-dimethyl tartrate, respectively, we obtained type I and II building blocks with orthogonal sets of protecing groups (4-8 steps, 38-56% overall yield).

Synthesis of orthogonally protected L-threo-beta-ethoxyasparagine.

Orthogonally protected L-threo-beta-ethoxyasparagine (Fmoc-EtOAsn(Trt)-OH, 1) was synthesized from diethyl (2S,3S)-2-azido-3-hydroxysuccinate 2 in eight steps as a building block for solid-phase peptide synthesis. The starting material is easily available in multi-gram scale from D-diethyltartrate. The transformation steps reported here are robust and scalable.

A novel protecting/activating strategy for beta-hydroxy acids and its use in convergent peptide synthesis.

beta-Hydroxy acids were reacted with hexafluoroacetone and carbodiimides to give carboxy-activated six-membered lactones in good yields. On reaction with amines, the corresponding amides were obtained. We demonstrate the following applications of this protecting/activating strategy: preparation of carboxamides in solution and on solid phase (both normal and reverse mode); recovery and reuse of the excess material in solid-phase synthesis; and convergent solid-phase peptide synthesis (CSPPS) with peptide segments bearing C-terminal Ser or Thr with very low levels of epimerization (<1%, HPLC).

Cysteine-S-trityl a key derivative to prepare N-methyl cysteines.

S-Trt Cys are used as precursors for the synthesis of protected NMe-Cys. N-Methylation of Alloc-Cys(Trt)-OH and Boc-Cys(Trt)-OH gives the corresponding N-methylated derivatives in good yields and purities, which can be further derivatized in solution to obtain a myriad of S-protected derivatives. To further broaden the scope of this methodology, the N (alpha)-amino protecting group of the NMe- S-protected Cys can be replaced easily either on the solid phase (from the Alloc precursor) or in solution (from the Boc precursor).

The synthesis of naturally occurring peptides and their analogs.

The number of peptide-based pharmaceuticals has increased enormously over recent years; some of these peptides are derived from natural sources, and many are large and complex. This review provides an overview of the current state of peptide synthesis methodology, focusing mainly on the synthesis of natural peptides and their analogs.

Simple machine-assisted protocol for solid-phase synthesis of depsipeptides.

A straightforward machine-assisted protocol for the synthesis of linear depsipeptides is reported. The synthesis was performed on a 433A Peptide Synthesizer (Applied Biosystems) using preprogrammed and optimized modules for Boc chemistry and without any need for hardware modification. The robustness of the protocol was demonstrated with 12 examples of 26-membered depsipeptides with single and multiple (up to 6) ester backbone substitutions.

p-Nitromandelic acid as a highly acid-stable safety-catch linker for solid-phase synthesis of peptide and depsipeptide acids.

[reaction: see text] p-Nitromandelic acid as a safety-catch linker for Boc/Bzl-SPPS of base-labile compounds like peptides and depsipeptides is described. This linker permits acidic removal of side-chain protection groups from the resin. For cleavage from the solid support, the p-nitro group was reduced with tin(II) chloride.

A new strategy for solid-phase depsipeptide synthesis using recoverable building blocks.

The technique of choice for synthesis of small-scale depsipeptides is on a solid support. However, if expensive monomers have to be incorporated, solid-phase synthesis can quickly turn out to be unattractive because of its low atom economy. Herein, we describe a new type of recoverable and reuseable alpha-hydroxy acid building block for solid-phase synthesis and its application in the synthesis of a number of small cyclic depsipeptides.