Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well‐defined three‐dimensional structures. Short synthetic peptide ...sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein‐like structures in water. However, short peptides can be induced to fold into protein‐like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine‐tune three‐dimensional structure. Such constrained cyclic peptides can have protein‐like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three‐dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties.
Short peptides can be constrained by cyclization to recreate key folded elements of protein structure, like β‐strands and β‐sheets, α‐helices, and turn motifs. Coupled with internal molecular constraints, cyclization has led to many protease‐resistant, potent and target‐selective, biologically active compounds for use in biology and medicine.
Caught in a ‘SNAr'e: A one‐step, high‐yielding, catalyst‐free method is described for N‐arylation of azoles and indoles from unactivated monofluorobenzenes. This SNAr reaction tolerates a wide range ...of substituents and can also generate halogenated N‐aryl products. The reaction can also be performed simultaneously with or subsequent to a copper‐ or palladium‐catalyzed cross‐coupling reaction in the same pot.
The first total synthesis and three-dimensional solution structure are reported for sanguinamide A, a thiazole-containing cyclic peptide from the sea slug H. sanguineus. Solution phase fragment ...synthesis, solid phase fragment assembly, and solution macrocyclization were combined to give (1) in 10% yield. Spectral properties were identical for the natural product, requiring revision of its structure from (2) to (1). Intramolecular transannular hydrogen bonds help to bury polar atoms, which enables oral absorption from the gut.
Reactivity studies of strong organic acids based on the replacement of one or both of the oxygens in benzoic acids with the trifluoromethanesulfonamide group are reported. Novel derivatives of these ...types of acids were synthesized in good yields. The generated
-triflylbenzamides were further functionalized through cross-coupling and nucleophilic aromatic substitution reactions. All compounds were stable in dilute aqueous solutions. Studies of stability under acidic and basic conditions are also reported.
Reactivity and regioselectivity of SNAr‐type fluorine substitution with azide in polyfluorosubstituted nitrobenzenes was studied both theoretically and experimentally. The obtained ...polyazido‐substituted nitrobenzene derivatives were extensively characterized by NMR, IR, HPLC, X‐ray, and DFT methods. It was found that the substitution with the azide nucleophile occurs first at the para‐ and the ortho‐positions to the NO2‐group and that transazidation reactions also occur here. Thermal decomposition of prepared azidonitrobenzenes was studied both in controlled (kinetic decay) and uncontrolled (explosion) modes. In case of the controlled thermal decomposition of ortho‐azidonitrobenzenes, benzofuroxans were found as major products of the reaction unless another azido group was adjacent to the furoxan moiety. The bursting power of azidonitrobenzenes was found to rise gradually with the number of the azide substituents in the aromatic ring.
Graphical showing a new concept for tuning the properties of environmentally benign primary explosives based on SNAr click‐chemistry.
In this contribution we attempt to answer a general question: can X-ray diffraction data combined with theoretical computations be a source of information about the thermodynamic properties of a ...given system? Newly collected sets of high-quality multi-temperature single-crystal X-ray diffraction data and complementary periodic DFT calculations of vibrational frequencies and normal mode vectors at the Γ point on the yellow and white polymorphs of di-methyl 3,6-di-chloro-2,5-di-hydroxy-terephthalate are combined using two different approaches, aiming to obtain thermodynamic properties for the two compounds. The first approach uses low-frequency normal modes extracted from multi-temperature X-ray diffraction data (normal coordinate analysis), while the other uses DFT-calculated low-frequency normal mode in the refinement of the same data (normal mode refinement). Thermodynamic data from the literature Yang
(1989),
B
, 312-323 and new periodic
DFT supercell calculations are used as a reference point. Both approaches tested in this work capture the most essential features of the systems: the polymorphs are enantiotropically related, with the yellow form being the thermodynamically stable system at low temperature, and the white form at higher temperatures. However, the inferred phase transition temperature varies between different approaches. Thanks to the application of unconventional methods of X-ray data refinement and analysis, it was additionally found that, in the case of the yellow polymorph, anharmonicity is an important issue. By discussing contributions from low- and high-frequency modes to the vibrational entropy and enthalpy, the importance of high-frequency modes is highlighted. The analysis shows that larger anisotropic displacement parameters are not always related to the polymorph with the higher vibrational entropy contribution.
Sequential regioselective N-arylations through high-yielding catalyst-free direct SNAr reactions of pentafluorobenzene derivatives with azole or indole derivatives are described. The N-arylated ...derivatives were further functionalized through a microwave-assisted cross-coupling reaction via C-H bond activation or Suzuki conditions. The order of the reactions could be reversed, proving full orthogonality between the reactions which led to well-defined fully substituted benzene derivatives.
The development of recognition molecules with antibody-like properties is of great value to the biotechnological and bioanalytical communities. The recognition molecules presented here are peptides ...with a strong tendency to form β-hairpin structures, stabilized by alternate threonines, which are located at one face of the peptide. Amino acids at the other face of the peptide are available for interaction with the target molecule. Using this scaffold, we demonstrate that recognition molecules can efficiently be designed in silico toward four structurally unrelated proteins, GFP, IL-1β, IL-2, and IL-6. On solid support, 10 different antibody-mimetic recognition molecules were synthesized. They displayed high affinity and no cross-reactivity, as observed by fluorescence microscopy. Stabilized variants were readily obtained by incorporation of azido acids and propargylglycine followed by cyclization via the Cu(I)-catalyzed alkyne–azide cycloaddition reaction. As this new class of antibody mimics can be designed toward essentially any protein, the concept is believed to be useful to a wide range of technologies. Here, their use in protein separation and in the detection of proteins in a sandwich-type assay is demonstrated.
A new type of lignin‐inspired polybenzylethersulfone (PBES) is synthesized by SNAr reaction in 75% yield. Success of the polymerization is confirmed by ATR‐IR, 1H, 13C NMR spectroscopy and MALDI‐TOF ...MS. The obtained polysulfone is solvent casted into a film which displays high thermal and chemical stability. Treatment with 33% HBr in acetic acid leads to degradation of the material. The isolated degradation products are identified and repolymerized back into PBES demonstrating the opportunity for chemical recycling of this new polymer.
A lignin‐inspired polybenzylethersulfone (PBES) is available from 4‐hydroxybenzyl alcohol via SNAr polymerization. The resulting high performance plastic from solvent evaporation casting is stable to >300 °C and resistant to a broad range of organic solvents and aqueous acid or bases. Hydrogen bromide degrades the polymer into products which after isolation may be repolymerized into polybenzylethersulfone (PBES) providing a recycling loop.
Abstract
A new type of lignin‐inspired polybenzylethersulfone (PBES) is synthesized by S
N
Ar reaction in 75% yield. Success of the polymerization is confirmed by ATR‐IR,
1
H,
13
C NMR spectroscopy ...and MALDI‐TOF MS. The obtained polysulfone is solvent casted into a film which displays high thermal and chemical stability. Treatment with 33% HBr in acetic acid leads to degradation of the material. The isolated degradation products are identified and repolymerized back into PBES demonstrating the opportunity for chemical recycling of this new polymer.
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