Polar Interactions between Stacked π Systems in Fluorinated 1,8‐Diarylnaphthalenes: Importance of Quadrupole Moments in Molecular Recognition

Cozzi, Franco; Ponzini, Francesco; Annunziata, Rita; Cinquini, Mauro; Siegel, Jay S.

doi:10.1002/anie.199510191

Cited by 298 publications

(221 citation statements)

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“…This is expected to be predominant only in concentrated solutions or when the interacting groups are brought together by some other interactions such as coulombic interactions or hydrogen bonds as in the designing of devices for molecular recognition, catalysis, and development of self-replicating molecules and molecular clips (20 -24). Such interactions are facilitated when the aromatic moieties are brought close to each other, making them substituents of the same molecule (25)(26)(27)(28). In this report, we demonstrate that following this designing principle, stacked nucleotide fluorophores that are in rapid equilibrium with the stretched forms can be synthesized quite easily.…”

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confidence: 79%

Synthesis and Characterization of Stacked and Quenched Uridine Nucleotide Fluorophores

Dhar

Bhaduri

1999

Journal of Biological Chemistry

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Since the seminal work of Weber and Laurence (1) with 1-anilinonaphthalene-8-sulfonic acid, extrinsic fluorescent probes have been extensively used to monitor various aspects of protein-ligand or enzyme-substrate interactions. Among others, these probes have been used (i) to establish the degree of polarity or hydrophobicity of a particular region of a protein, (ii) to measure the distance between groups on protein surface, (iii) to measure the extent of flexibility of protein in solution, (iv) to measure the rate of very rapid conformational transitions, and (v) to measure kinetic constants of interaction between protein and ligand (2). To facilitate these studies, a variety of derivatized fluorescent ligands or substrate analogs have been synthesized over the years without any serious attention being given to their solution conformations or their transitions to new conformations on interaction with the target proteins. Such conformational transitions are often crucial steps in biological interactions as typically exemplified by NAD, the common cofactor for a very large number of dehydrogenases. The molecule exhibits reversible stacking between the adenine and pyridine moiety with both the open and the closed forms in rapid interconversionary equilibrium in aqueous solutions (3, 4). During catalysis, NAD takes a totally extended conformation on the enzyme surface; the conserved tertiary structure of the pyridine nucleotide binding site being a very characteristic feature of all these oxidoreductases (5).Etheno-ATP was originally synthesized as a fluorescent analog of ATP. It had a high quantum yield and a long fluorescence lifetime and could be used to follow ATP interactions primarily by polarization studies (6 -8). In contrast, as in case of NAD, significant population of etheno-NAD was in a folded conformation in aqueous solution as a result of aromatic interactions between the pyridine and the modified adenine moiety, leading to dynamic collisional quenching of fluorescence and short fluorescence life-time (9). This stacked and quenched fluorophore was brilliantly used to establish negative co-operativity for glyceraldehyde-3-phosphate dehydrogenase from rabbit muscle for the binding of the tetrameric apoenzyme to the coenzyme. The conformational transition of etheno-NAD from folded to stretched conformation as reflected by its enhanced fluorescence on interaction with the target protein was the monitoring parameter for this purpose (10). Although stacked fluorophore with quenched fluorescence can be of immense use in protein-ligand binding studies, as is exemplified by etheno-NAD, it is surprising to note that no deliberate effort has so far been made to design such compounds taking advantage of the potential aromatic interaction between the attached fluorophore and a suitable moiety of the desired biomolecule.The interaction between aromatic rings is of wide chemical and biological interest, because it plays important roles in vital biological processes, such as stabilization of protein and nucleic acid s...

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confidence: 79%

Synthesis and Characterization of Stacked and Quenched Uridine Nucleotide Fluorophores

Dhar

Bhaduri

1999

Journal of Biological Chemistry

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“…[455,456] Das Addukt des C-H-aciden Trifluormethans mit Benzol wurde schwingungsspektroskopisch wie auch durch Ab-initio-Rechnungen charakterisiert. [457] Die Schwäche der CH-p-Wechselwirkung macht es schwierig, sie bei supramolekularen Komplexen in Lösung eindeutig nachzuweisen.…”

Section: Supramolekulare Komplexeunclassified

Bindungsmechanismen in supramolekularen Komplexen

Schneider

2009

Angewandte Chemie

185

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Kräfte‐Sammelsurium: Supramolekulare Komplexe, wie der gezeigte, beruhen meist auf einer Kombination unterschiedlichster Wechselwirkungen, wie Ionenpaarbildung, Wasserstoffbrücken und Stapelwechselwirkungen. Die nicht immer einfache Charakterisierung von Natur und Stärke der intermolekularen Kräfte liefert Beiträge zum Verständnis biomimetischer Systeme wie auch zum Design von synthetischen Rezeptoren, Wirkstoffen und intelligenten Materialien. Die supramolekulare Chemie hat in den letzten Jahren eine enorme Ausdehnung erfahren, sowohl mit Blick auf mögliche Anwendungen wie auch auf analoge biologische Systeme. Bildung und Funktion supramolekularer Komplexe werden durch eine Vielzahl von oft schwer zu differenzierenden nichtkovalenten Kräften bestimmt. Ziel dieses Aufsatzes ist es, die entscheidenden Wechselwirkungsmechanismen zusammenhängend darzustellen und das Gesamtgebiet auf diese Weise zu klassifizieren. Als Beispiele werden meist organische Wirt‐Gast‐Komplexe gewählt, unter Berücksichtigung auch von biologisch relevanten Fragestellungen. Das Verständnis und die Quantifizierung der intermolekularen Wechselwirkungen ist für die rationale Planung neuer supramolekularer Systeme, einschließlich intelligenter Materialien, ebenso von Bedeutung wie für die Entwicklung neuer Wirkstoffe.

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“…This is due to the increase of the vertical electrostatic interactions between the fluorine atom and the C-H group of neighboring benzene rings, together with the linear C-H … F interactions, because the acidity of C-H proton could be increased by the substitution of fluorine atom. On the other hand, it has been reported 17,18) that the addition of fluorine atom in the interaction between the aromatic and perfluoroaromatic compounds decreases the repulsion in the stacked ground state upon removal of electron density from the ring. Also, the interplay 1262…”

Section: Resultsmentioning

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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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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Polar Interactions between Stacked π Systems in Fluorinated 1,8‐Diarylnaphthalenes: Importance of Quadrupole Moments in Molecular Recognition

Cited by 298 publications

References 45 publications

Synthesis and Characterization of Stacked and Quenched Uridine Nucleotide Fluorophores

Synthesis and Characterization of Stacked and Quenched Uridine Nucleotide Fluorophores

Bindungsmechanismen in supramolekularen Komplexen

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

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