Synthesis of a complete set of l-difluorophenylalanines, l-(F2)Phe, as molecular explorers for the CH/π interaction between peptide ligand and receptor

It is well documented that noncovalent aromatic-aromatic interactions are important in determining the molecular conformation, stability and activity of biological macromolecules. 1,2) In globular proteins, the close interactions between the aromatic amino acids Phe, Tyr and Trp often form a part of a hydrophobic pocket to bind an aromatic substrate. [3][4][5] As for the aromatic interaction of phenylalanine (Phe) residues in proteins, either an off-center displaced face-toface or a T-shaped edge-to-face structure has been considered as the preferred orientation since it is nearly isoenergetic.6) In the latter structure, the acidic C-H group on the benzene ring acts as a weak hydrogen-bonding donor and the p-electron on the ring acts as an acceptor. This means that the benzene ring can serve as a pocket accepting the cationic molecule through the cation … p interaction.2,7) On the other hand, the benzene ring in which H atoms are substituted by fluorine atoms could serve as an anion-acceptor through the anion … p interaction, 2,8) based on the crystal structure of C 6 H 6 · C 6 F 6 complex at 30 K. 9) Thus, the benzene ring can be said to form different noncovalent interactions by replacing the hydrogen atoms with other atoms, information on the association pattern of heteroatom-substituted benzene rings in the crystal structure is useful for designing an acceptor molecule to recognize a specified aromatic molecule.Herein, we report the crystal structures of four kinds of fluorophenylalanines (3-fluoro-, 4-fluoro-, 2,4,5-trifluoro-, and 3,4,5-trifluoroPhes). The observed structural features make it clear how the noncovalent interaction of benzene rings is affected by the substituted position and number of fluorine atoms. Especially, we focus on (i) how the acidity of benzene C-H proton is activated by the substitution of fluorine atom, and (ii) which donor group (benzene C-H or amino N-H) participates preferentially in the interaction with the electronegative fluorine atom. The present results are of interest to learn why thrombin receptor-derived peptide SFLLRNP (Ser-Phe-Leu-Leu-Arg-Asn-Pro) is able to activate the activity several fold by the substitution of para-fluoroPhe for Phe-2.10) The atomic numbering of the four kinds of fluorophenyl-alanines used in this work is given in Fig. 1. ExperimentalMaterial Three kinds of monofluoro-L-Phe were purchased from Wako Pure Chemical (Tokyo). Di-and trifluoroPhes were prepared according to the previously reports.11,12) The purities were verified by analytical RP-HPLC.X-Ray Crystal Analysis Among various attempts to crystallize a series of mono-, di-, and tri-fluoroPhes, single crystals of 3-and 4-monofluoro and 2,4,5-and 3,4,5-trifluoroPhes were obtained from the slow evaporation of aqueous ethanol or methanol solution at room temperature in the form of transparent needles. The X-ray measurements were made on a Rigaku AFC-5 diffractometer with graphite-monochromated CuKa radiation (lϭ 1.5418 Å) using a w-2q scan mode for 3-fluoroPhe and a Brucker SMART APEX CCD diffr...

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“…Di-and trifluoroPhes were prepared according to the previously reports. 11,12) The purities were verified by analytical RP-HPLC.…”

Section: Methodsmentioning

confidence: 99%

Aggregation Feature of Fluorine-Substituted Benzene Rings and Intermolecular C-H...F Interaction: Crystal Structure Analyses of Mono- and Trifluoro-L-phenylalanines

Kishima

Minoura

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The resulting attractive CH-π interaction [24,25] has been used systematically to strengthen the binding of a fluorine-modified heptapeptide to its receptor by edge-to-face interactions [26] (Figure 9.1). Lone electron pairs can not only act as hydrogen bridge acceptors but also as electron-rich aromatic π-electron systems.…”

Section: Hydrogen Bonding and Electrostatic Interactionsmentioning

confidence: 99%

“…The Figure 9.1 Enhancement of the binding of a 3,4difluorophenylalanine-containing peptide to its receptor by an edge-to-face CH-π interaction [26]. .2 Uracil and its fluorinated carbocyclic analog 1,3-difluorobenzene (a) have a similar distribution profile of partial charges q (mapped on the electron density surface; blue and red denote negative and positive partial charges, respectively; B3LYP/6-31G * level of theory) [32], but the absolute values for, for example, the 2,4-difluorotoluene analog (b) are significantly smaller than for deoxythymidine (c) [33].…”

Section: Hydrogen Bonding and Electrostatic Interactionsmentioning

confidence: 99%

Pharmaceuticals and Other Biomedical Applications

Kirsch

2013

Modern Fluoroorganic Chemistry

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“…NMR spectra were recorded on a 600 MHz Bruker NMR spectrometer ( 1 H 600 MHz, 19 19 F 282 MHz). The Bruker NMR spectrometers were equipped with inverse 5 mm TBI and 5 mm QNP probe head.…”

Section: Generalmentioning

confidence: 99%

“…Recently, it was disclosed that hydrophobic interactions are far more essential in ligand-receptor interactions than assumed, while the influence of hydrogen bonding was overestimated [17,18]. The mechanism of these hydrophobic interactions, however, was never elucidated in detail [19]. Sidechain phenyl groups play an essential role in ligand-receptor interactions.…”

Section: Introductionmentioning

confidence: 99%

Fluoro‐modified chemotactic peptides: fmlf analogues

Koksch

Dahl

Radics

et al. 2003

Journal of Peptide Science

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A small library of peptide analogues of the chemotactic tripeptide For-Met-Leu-Phe-NH2 modified by substitution of Leu at position 2 by three different fluorinated amino acids varying in content of fluorine, length of the fluorinated side chain, and alkylation degree at the alpha-carbon atom was synthesized. The influence of the fluorine substitution on the biological activity was investigated by measuring the oxidative activity of neutrophils using a luminol-dependent chemiluminescence assay.

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Synthesis of a complete set of l-difluorophenylalanines, l-(F2)Phe, as molecular explorers for the CH/π interaction between peptide ligand and receptor

Cited by 17 publications

References 5 publications

Aggregation Feature of Fluorine-Substituted Benzene Rings and Intermolecular C-H...F Interaction: Crystal Structure Analyses of Mono- and Trifluoro-L-phenylalanines

Aggregation Feature of Fluorine-Substituted Benzene Rings and Intermolecular C-H...F Interaction: Crystal Structure Analyses of Mono- and Trifluoro-L-phenylalanines

Pharmaceuticals and Other Biomedical Applications

Fluoro‐modified chemotactic peptides: fmlf analogues

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