Fluorinated Triazole Foldamers: Folded or Extended Conformational Preferences

Abstract

Fluorinated peptidomimetic foldamers are still in their infancy. We report here the easy access to fluorinated triazolamers based on 2-amino-3,3,3-trifluoropropyl-1,4-triazolyl acetic acid (CF 3 À 1,4-Tz) and on aminomethyl-1,4-triazolyl-difluoroacetic acid (1,4-TzÀ CF 2). Both CF 3 À 1,4-Tz and 1,4-TzÀ CF 2 amino acids were efficiently prepared by copper(I)-catalyzed Huisgen 1,3dipolar cycloaddition. Their conformational preferences were studied by 2D NMR analyses and molecular dynamic simulations. Foldamers based on CF 3 À 1,4-Tz amino acids are capable of adopting short multi-stranded β-sheet-like structures that are maintained by electrostatic interactions between the triazole proton and N2 atom of neighboring subunits. On the contrary, foldamers based on 1,4-TzÀ CF 2 units adopt elongated β-strandlike structures, stabilized by electrostatic interaction between fluorine atoms and their neighboring protons.

“Fluorine Effects” in Conformational Orchestration of α/β Hybrid Peptide with a 9‐membered Pseudo β‐Turn Motif

“…[9,10] Biochemists considered the properties and functions of peptides with nonproteinogenic motifs bearing one or more fluorine atoms on the side chain. [11][12][13] Furthermore, the concept has been extended to many challenging research areas such as foldamers [14][15][16][17][18] (artificial peptides) and protein engineering. [19,20] Fluorine, a bioisostere to hydrogen, has a comparable van der Waals's radius (r H = 1.2 Å and r F = 1.35 Å).…”

Composition and Conformation of Hetero‐ versus Homo‐Fluorinated Triazolamers Influence their Activity on Islet Amyloid Polypeptide Aggregation

“…Then we performed the self-assembly of this architecture and carried out conformational studies of these new foldamers (Figure 1, compounds 1, 2). [44] Oligomers of 1,4-Tz, called triazolamers, have been rarely reported in literature, especially in medicinal chemistry. Triazoles act as trans-amide mimetics with higher stability to hydrolysis.…”

“…Our fluorinated homotriazolamers based on the assembly of tri and four 1,4-TzÀ CF 2 adopt elongated β-strand-like structures. [44] Herein we present the rational design, synthesis, and conformational studies of new fluorinated foldamers based on 1,4-TzÀ CF 2 mixed with natural amino acids, which we call heterotriazolamers (Figure 1, compounds 3-7). Their conformation preferences and ability to modulate the hIAPP aggregation process have been compared with our previous homotriazolamers (Figure 1, compounds 1-2).…”

“…The stabilizing electrostatic interactions between the fluorine atoms and the neighboring triazole and the NH of the successive amino acid induced extended conformation. Then we performed the self‐assembly of this architecture and carried out conformational studies of these new foldamers (Figure 1, compounds 1 , 2 ) [44] . Oligomers of 1,4‐Tz, called triazolamers, have been rarely reported in literature, especially in medicinal chemistry.…”

Fluorine Labeling of ortho-Phenylenes to Facilitate Conformational Analysis

“…Of course, biochemistry, the inspiration for the field, has long struggled with this same problem. One solution is the use of 19 F labeling and thus analysis by 19 F NMR spectroscopy. − Indeed, examples of fluorinated peptidic foldamers have been reported, − as have a handful of examples of fluorinated aromatic foldamers. − In some cases, 19 F NMR spectroscopy provides new insight into their behavior. ,,− …”