Controlling the outcome of overacylation of N-protected aminooxyacetic acid during the synthesis of an aminooxy-peptide for chemical ligation

An aminooxy-containing peptide, the nucleophile partner for oxime ligations, is usually grafted on a NH₂-peptide resin by activating a protected aminooxyacetic acid as an active ester. Here, we have shown that its subsequent coupling to NH₂-peptide resin competes with the overacylation of the -NH-O- nitrogen and that the overacylation level increases with the basicity of the reaction mixture. Moreover, we found that overacylation is prevented when the COOH of the Aoa-derivatives is engaged in an amide bond.     

A bifunctional chelator featuring the DOTAM-Gly-l-Phe-OH structural subunit: en route toward homo- and heterobimetallic lanthanide(III) complexes as PARACEST MRI contrast agents

A new synthesis of a bifunctional chelator possessing DOTAM-Gly-l-Phe-OH and DO3A chelating cages interconnected by an oligoamide chain has been achieved via HBTU-mediated coupling from easily accessible building blocks. Both homo- and heterobimetallic lanthanide(III) complexes derived from this bifunctional chelator have been prepared in moderate yields. The CEST spectrum acquired for homobimetallic Eu³⁺ complex showed this molecule to be a promising PARACEST MRI contrast agent whereas the Eu³⁺/Tm³⁺ heterobimetallic complex lacked a useful CEST signal.     

Efficient solid-phase synthesis of cyclic RGD peptides under controlled microwave heating

Cyclic RGD peptides are potent antagonists for the α_vβ₃ integrin receptor. In this Letter, microwave-assisted solid-phase synthesis of cyclic RGD peptides is described. In a coupling reaction between Fmoc-Arg(Pbf)-OH and high-loading H-Gly-Trt(2-Cl) resin, multiple coupling reactions were required for completion under the conventional HBTU activation. We found that the use of COMU, a new coupling reagent, under microwave heating to 50 °C accelerated the reaction even inside the resin. This method was applicable to the synthesis of linear pentapeptides, H-Asp(OtBu)-Xxx-Yyy-Arg(Pbf)-Gly-OH (Xxx = d-Phe(p-Br) or d-Tyr, Yyy = Lys(Boc) or MeVal). Cyclization of these peptides followed by deprotection gave the desired cyclic RGD peptides with high purity.     

Synthesis,characterization and complexation studies of bis-oxy biphenyl based novel diamides

A series of bis-oxy biphenyl based diamides have been synthesized and characterized from spectral and XRD data. All the diamides form charge-transfer (CT) complex with 7,7,8,8-tetracyanoquinodimethane (TCNQ).     

Synthesis of an olefin-containing cyclic peptide using the solid-phase Horner-Emmons reaction

Linear and cyclic olefin peptides containing the substrate sequence for human T-cell leukemia virus type-1 (HTLV-1) were efficiently synthesized on a solid support using the Horner-Emmons reaction. The precursor peptide aldehyde was prepared by oxidation of the corresponding peptide alcohol with Dess-Martin periodinane. The oxidation reaction proceeded quantitatively on a cross-linked ethoxylate acrylate resin (CLEAR) support instead of a polystyrene-based support. Cyclization on the solid support was achieved via an amide bond formation mediated by EDC/HOAt to yield a single major product. The linear olefin peptide was cleaved by HTLV-1 protease at the scissile site, whereas the cyclic olefin peptide functions as a competitive inhibitor rather than a substrate.     

A one-pot preparation of N-2-mercaptobenzoyl-amino amides

The HIV-1 nucleocapsid (NCp7), structurally defined by zinc-binding domains, participates in crucial stages of the HIV-1 lifecycle and is mutationally nonpermissive, making it an attractive anti-HIV target. Mode of action studies have shown that the secondary structure and activity of NCp7 can be disrupted by acyl transfer from N-2-mercaptobenzoyl-amino amides. We have developed an improved one-pot reaction that affords N-2-mercaptobenzoyl-amino acids on multi-gram scales. This synthetic route allows for rapid modular construction and has greatly expanded the scope of easily accessible potential NCp7 inhibitors.     

‘Bis-ornithine’ (2,2-bis(aminopropyl)glycine): a new tetravalent template for assembling different functional peptides

Synthesis of bis-ornithine, a new C^α,α-disubstituted α-amino acid bearing orthogonally protected α and δ amine groups is reported. Bis-ornithine (bisOrn) and dipeptides containing bis-ornithine have been synthesized in solution up to multigram scale. As a first example, one of these compounds Boc-βAla-bisOrn(Alloc)₂-OH has been attached to a solid support and used as template for the synthesis of a symmetrical assemblage of peptides.     

The role of the histidine residue in the coordination abilities of peptides with a multi-histidine sequence towards copper(II) ions

Cu²⁺ complexes with peptides containing three histidine residues have very specific metal binding abilities and can mimic the structures of various multi-histidine metal binding sites in proteins. The main goal of the work concerns the investigations of coordination abilities of the group of N-terminally protected Ac-His-Arg-His-Gly-His-Gly, Ac-His-Gly-His-Arg-His-Gly, Ac-Gly-His-His-Arg-His-Gly and Ac-His-His-Gly-His-Arg-Gly, and their unprotected analogs His-Arg-His-Gly-His-Gly, His-Gly-His-Arg-His-Gly, Gly-His-His-Arg-His-Gly and His-His-Gly-His-Arg-Gly towards Cu²⁺ ions. Detailed spectroscopic (UV/Vis, CD and EPR) and potentiometric studies have been made. The stoichiometry and binding mode for each ligand–Cu²⁺ system were determined.     

Phenylglycine racemization in Fmoc-based solid-phase peptide synthesis: Stereochemical stability is achieved by choice of reaction conditions

Phenylglycine-containing peptides have broad applications in medicinal chemistry, but their synthetic accessibility is complicated by the risk of epimerization during solid-phase peptide synthesis (SPPS). Phenylglycine is therefore often considered a troublesome residue. This work studies the extent of Phg racemization under different Fmoc-SPPS reaction conditions. It is shown that the base-catalyzed coupling of Fmoc-Phg is the critical step for racemization. However, racemization can be reduced to a negligible level if DEPBT or COMU combined with TMP or DMP are employed during this step. Resin-bound peptides are remarkably resistant against epimerization during extended incubation under basic conditions and the free peptides were stable in buffer solutions used for biological assays.