Exploration of the role of phenylalanine in the thrombin receptor tethered-ligand peptide by substitution with a series of trifluorophenylalanines

Ayami Matsushima, T. Fujita, K. Okada, N. Shirasu, Takeru Nose, Y. Shimohigashi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

The thrombin receptor-tethered ligand SFLLRNP (abbreviation formed by one letter amino acid codes expressing Ser-Phe-Leu-Leu-Arg-Asn-Pro) consists of the Phe-2 residue essential for the receptor activation. In order to explore the molecular characteristics of this Phe-2-phenyl, a series of trifluorophenylalanines [(F 3 )Phe] was incorporated into this S/Phe/LLRNP for evaluation of their ability to induce the human platelet aggregation. A complete set of (F 3 )Phe in the L-configuration, namely, (2,3,4-F 3 )Phe, (2,3,5-F 3 )Phe, (2,3,6-F 3 )Phe, (2,4,5-F 3 )Phe, (2,4,6-F 3 )Phe, and (3,4,5-F 3 )Phe, was prepared from trifluorobenzyl bromides and diethyl acetamidomalonate. S/(2,3,4-F 3 )Phe/LLRNP was equipotent to S/Phe/LLRNP, while (2,4,5-F 3 )Phe-containing analog was almost twice as potent as those. (2,4,6-F 3 )Phe-analog exhibited about a half of the activity of S/Phe/LLRNP. (3,4,5-F 3 )Phe-, (2,3,5-F 3 )Phe-, and (2,3,6-F 3 )Phe-analogs were very weak. The analysis of these assay results suggested that Phe-2-phenyl of SFLLRNP is in the edge-to-face CH/π interaction with the receptor aromatic group, utilizing the Phe-2-phenyl edge along with benzene hydrogens at position 2-3 or 5-6. The computer-assisted semi-empirical molecular orbital calculations by MOPAC showed that the fluorine atom decreases the electron density of its ortho, meta, and para hydrogens, and thus increases their acidity more strongly in that order. All these suggested that H → F replacements reinforce the edge-to-face CH/π interaction to enhance biological activity. The H → F replacement on the Phe-phenyl group was found to render an effective structural examination; i.e., to identify the hydrogens in the CH/π interaction, and to intensify the CH/π interaction.

Original languageEnglish
Pages (from-to)2531-2538
Number of pages8
JournalBulletin of the Chemical Society of Japan
Volume73
Issue number11
DOIs
Publication statusPublished - Nov 1 2000

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

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