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<p>Recent identification of long chain conjugates of amino acids, such as <i>N</i>-acyl derivatives, in mammalian brain has generated great interest in investigating their structural features, physico-chemical properties and interaction with biomolecules. In this study, we report the synthesis of <i>N</i>-acyl derivatives of phenylalanine and tyrosine, namely <i>N</i>-nonanoyl-L-phenylalanine (N9-Phe) and <i>N</i>-nonanoyl-L-tyrosine (N9-Tyr), as well as the corresponding esters, nonyl-L-phenylalaninate (9-Phe), and nonyl-L-tyrosinate (9-Tyr), and also their structural and physicochemical characterization. Fluorescence and isothermal titration calorimetry (ITC) studies revealed that 9-Tyr and N9-Tyr form micelles at higher concentrations than 9-Phe and N9-Phe, respectively. Differential scanning calorimetric studies showed that 9-Tyr exhibits a higher phase transition temperature (<i>T</i><sub>t</sub>) than 9-Phe, while N9-Phe displayed a higher <i>T</i><sub>t</sub> than N9-Tyr. Structural analysis by single-crystal X-ray diffraction revealed notable differences in the ester and amide derivatives with respect to molecular structure, packing motifs and hydrogen bonding interactions, leading to differences in supramolecular organization. ITC studies revealed that the cationic 9-Phe and 9-Tyr bind to DNA, with the former exhibiting two types of binding, characterized by stronger and weaker binding constants – which are governed by enthalpic and entropic forces, respectively – whereas 9-Tyr binds with a single, enthalpically-driven binding constant. These observations suggest that the long-chain esters of Phe and Tyr may have potential application in gene delivery.</p> Graphical abstract <p>Studies on the self-assembly, thermotropic phase behavior, and crystal structures of C9-alkyl/acyl derivatives of phenylalanine and tyrosine reveal that the hydroxyl group of tyrosine strongly influences their structural features and supramolecular interactions. The C9-esters of both Tyr and Phe bind DNA quite strongly, suggesting potential application in gene delivery.</p> <p></p>

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Structure, self-assembly and thermotropic phase behavior of N-acyl and O-alkyl conjugates of phenylalanine and tyrosine: interaction with DNA

  • 期刊论文

  • 发表日期：

    2026年4月21日

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  • Konga Manasa,
  • Dokku Sivaramakrishna,
  • Suman K Choudhury,
  • Musti J Swamy

摘要

Recent identification of long chain conjugates of amino acids, such as N-acyl derivatives, in mammalian brain has generated great interest in investigating their structural features, physico-chemical properties and interaction with biomolecules. In this study, we report the synthesis of N-acyl derivatives of phenylalanine and tyrosine, namely N-nonanoyl-L-phenylalanine (N9-Phe) and N-nonanoyl-L-tyrosine (N9-Tyr), as well as the corresponding esters, nonyl-L-phenylalaninate (9-Phe), and nonyl-L-tyrosinate (9-Tyr), and also their structural and physicochemical characterization. Fluorescence and isothermal titration calorimetry (ITC) studies revealed that 9-Tyr and N9-Tyr form micelles at higher concentrations than 9-Phe and N9-Phe, respectively. Differential scanning calorimetric studies showed that 9-Tyr exhibits a higher phase transition temperature (Tt) than 9-Phe, while N9-Phe displayed a higher Tt than N9-Tyr. Structural analysis by single-crystal X-ray diffraction revealed notable differences in the ester and amide derivatives with respect to molecular structure, packing motifs and hydrogen bonding interactions, leading to differences in supramolecular organization. ITC studies revealed that the cationic 9-Phe and 9-Tyr bind to DNA, with the former exhibiting two types of binding, characterized by stronger and weaker binding constants – which are governed by enthalpic and entropic forces, respectively – whereas 9-Tyr binds with a single, enthalpically-driven binding constant. These observations suggest that the long-chain esters of Phe and Tyr may have potential application in gene delivery.

Graphical abstract

Studies on the self-assembly, thermotropic phase behavior, and crystal structures of C9-alkyl/acyl derivatives of phenylalanine and tyrosine reveal that the hydroxyl group of tyrosine strongly influences their structural features and supramolecular interactions. The C9-esters of both Tyr and Phe bind DNA quite strongly, suggesting potential application in gene delivery.