Design and Synthesis of Novel ¹⁹F‑Amino Acid: A Promising ¹⁹F NMR Label for Peptide Studies

Novel aliphatic ¹⁹F-substituted amino acid was designed as a ¹⁹F NMR label for peptide studies. The synthesis was performed in 11 steps and 9% overall yield from a commercially available starting material. The key transformation was a decarboxylative fluorination of an aliphatic carboxylic acid with XeF₂ in C₆F₆

Incorporation of <i>cis</i>- and <i>trans</i>-4,5-Difluoromethanoprolines into Polypeptides

Substituted prolines exert diverse effects on the backbone conformation of proteins. Novel difluoro-analogues were obtained by adding difluorocarbene to N-Boc-4,5-dehydroproline methyl ester, which gave the <i>trans</i>-adduct as the sole product with 71% yield. Upon cleavage of the N-protection group the free amino acid decomposed rapidly. Its incorporation into the proline-rich cell-penetrating “sweet arrow peptide” was thus accomplished using a dipeptide strategy. Two building blocks, containing either <i>cis</i>- or <i>trans</i>-4,5-difluoromethanoproline, were obtained by difluorocyclopropanation of the aminoacyl derivatives of 4,5-dehydroproline. The resulting dipeptides were stable under standard conditions of Fmoc solid phase peptide synthesis and, thus, suitable to study conformational effects

The Most Reactive Amide As a Transition-State Mimic For <i>cis</i>–<i>trans</i> Interconversion

1-Azatricyclo­[3.3.1.1^3,7]­decan-2-one (<b>3</b>), the parent compound of a rare class of 90°-twisted amides, has finally been synthesized, using an unprecedented transformation. These compounds are of special interest as transition-state mimics for the enzyme-catalyzed <i>cis</i>–<i>trans</i> rotamer interconversion of amides involved in peptide and protein folding and function. The stabilization of the amide group in its high energy, perpendicular conformation common to both systems is shown for the rigid tricyclic system to depend, as predicted by calculation, on its methyl group substitution pattern, making <b>3</b> by some way the most reactive known “amide”

1-Alkyl-5-((di)alkylamino) Tetrazoles: Building Blocks for Peptide Surrogates

An approach to the synthesis of 1-alkyl-5-((di)­alkylamino)­tetrazoles by nucleophilic substitution in 1-alkyl-5-sulfonyltetrazoles with anions generated from the primary or secondary amines was developed. Tolerance of the method to the presence of some functional groups (i.e., protected amine) in both components of the reaction was demonstrated. Obtained tetrazoles are promising building blocks for the design of peptide surrogates, in particular, for replacement approaches of alkyl urea derivatives

Synthesis and Structural Analysis of Angular Monoprotected Diamines Based on Spiro[3.3]heptane Scaffold

The synthesis of all stereoisomers of spiro[3.3]­heptane-1,6-diamines suitably protected for use as building blocks in drug discovery is reported. Structural analysis revealed the similarity between the spiro[3.3]­heptane and cyclohexane scaffolds. Comparison of the distance between functional groups and their spatial orientation proved that (1<i>S</i>,4<i>r</i>,6<i>R</i>)- and (1<i>R</i>,4<i>r</i>,6<i>S</i>)-1,6-disubstituted spiro­[3.3]­heptanes can be considered as restricted surrogates of <i>cis</i>-1,4-disubstituted cyclohexane derivatives. Similarly, (1<i>S</i>,4<i>s</i>,6<i>R</i>)- and (1<i>R</i>,4<i>s</i>,6<i>S</i>)-1,6-disubstituted spiro[3.3]­heptanes are the restricted surrogates of <i>trans</i>-1,3-disubstituted cyclohexanes. Such replacement can be recommended for use in optimization of ADME parameters of lead compounds in drug discovery

The Most Reactive Amide As a Transition-State Mimic For <i>cis</i>–<i>trans</i> Interconversion

1-Azatricyclo­[3.3.1.1^3,7]­decan-2-one (<b>3</b>), the parent compound of a rare class of 90°-twisted amides, has finally been synthesized, using an unprecedented transformation. These compounds are of special interest as transition-state mimics for the enzyme-catalyzed <i>cis</i>–<i>trans</i> rotamer interconversion of amides involved in peptide and protein folding and function. The stabilization of the amide group in its high energy, perpendicular conformation common to both systems is shown for the rigid tricyclic system to depend, as predicted by calculation, on its methyl group substitution pattern, making <b>3</b> by some way the most reactive known “amide”

Imidazole-2yl-Phosphonic Acid Derivative Grafted onto Mesoporous Silica Surface as a Novel Highly Effective Sorbent for Uranium(VI) Ion Extraction

A new imidazol-2yl-phosphonic acid/mesoporous silica sorbent (ImP­(O)­(OH)₂/SiO₂) was developed and applied for uranium­(VI) ion removal from aqueous solutions. The synthesized material was characterized by fast kinetics and an extra-high adsorption capacity with respect to uranium. The highest adsorption efficiency of U­(VI) ions was obtained for the reaction system at pH 4 and exceeded 618 mg/g. The uranium­(VI) sorption proceeds quickly in the first step within 60 min of the adsorbent sites and ion interactions. Moreover, the equilibrium time was determined to be 120 min. The equilibrium and kinetic characteristics of the uranium­(VI) ions uptake by synthesized sorbent was found to follow the Langmuir–Freundlich isotherm model and pseudo-second-order kinetics rather than the Langmuir, Dubinin–Radushkevich, and Temkin models and pseudo-first-order or intraparticle diffusion sorption kinetics. The adsorption mechanism for uranium on the sorbent was clarified basing on the X-ray photoelectron spectroscopy (XPS) analysis. The model of UO₂²⁺ binding to surface of the sorbent was proposed according to the results of XPS, i.e., a 1:1 U-to-P ratio in the sorbed complex was established. The regeneration study confirms the ImP­(O)­(OH)₂/SiO₂ sorbent can be reused. A total of 45% of uranium ions was determined as originating from the sorbent leaching in the acidic solutions, whereas when the basic solutions were used, the removal efficiency was 12%

Structural characteristics of TP10.

<p>Summary of features related to the bipartite character of the hybrid peptide TP10 (positions labeled with CF₃-Bpg are marked in red).</p

Cellular uptake of TP10.

<p>(A, B) Internalization of TP10 WT and of two representative ¹⁹F-labeled analogs Ile8→ <b><i>L</i></b><b>-</b>CF₃-Bpg (C), and Ile20→ <b><i>L</i></b><b>-</b>CF₃-Bpg (D) by HeLa cells. The cells were incubated with 10 µM peptide at 37°C for 30 min.</p

Secondary structure of TP10-WT bound to DMPC/DMPG vesicles evaluated from the CD spectrum (P/L = 1∶50, see Figure S1 A/B in File S1 for details).

a<p>NRMSD = normalized root mean square deviation between calculated and experimental CD spectra.</p