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Proton Affinity and Conformational Integrity of a 24-Atom Triazine Macrocycle across Physiologically Relevant pH.
Menke, Alexander J; Jacobus, Zachary P; Claton, Liam E; Annunziata, Onofrio; Capelli, Riccardo; Pavan, Giovanni M; Simanek, Eric E.
Afiliación
  • Menke AJ; Department of Chemistry & Biochemistry, Texas Christian University, Fort Worth, Texas 76129, United States.
  • Jacobus ZP; Department of Chemistry & Biochemistry, Texas Christian University, Fort Worth, Texas 76129, United States.
  • Claton LE; Department of Chemistry & Biochemistry, Texas Christian University, Fort Worth, Texas 76129, United States.
  • Annunziata O; Department of Chemistry & Biochemistry, Texas Christian University, Fort Worth, Texas 76129, United States.
  • Capelli R; Department of Biosciences, Università degli Studi di Milano, Via Celoria 26, Milan 20133, Italy.
  • Pavan GM; Department of Innovative Technologies, University of Applied Sciences and Arts of Southern Switzerland, Polo Universitario Lugano, Lugano-Viganello 6962, Switzerland.
  • Simanek EE; Department of Applied Science and Technology, Politecnico di Torino, Torino 10129, Italy.
J Org Chem ; 89(4): 2467-2473, 2024 Feb 16.
Article en En | MEDLINE | ID: mdl-38299798
ABSTRACT
For 24-atom triazine macrocycles, protonation of the heterocycle leads to a rigid, folded structure presenting a network of hydrogen bonds. These molecules derive from dynamic covalent chemistry wherein triazine monomers bearing a protected hydrazine group and acetal tethered by the amino acid dimerize quantitatively in an acidic solution. Here, lysine is used, and the product is a tetracation. The primary amines of the lysine side chains do not interfere with quantitative yields of the desired bis(hydrazone) at concentrations of 5-125 mg/mL. Mathematical modeling of data derived from titration experiments of the macrocycle reveals that the pKa values of the protonated triazines are 5.6 and 6.7. Changes in chemical shifts of resonances in the 1H NMR spectra corroborate these values and further support assignment of the protonation sites. The pKa values of the lysine side chains are consistent with expectation. Upon deprotonation, the macrocycle enjoys greater conformational freedom as evident from the broadening of resonances in the 1H and 13C NMR spectra indicative of dynamic motion on the NMR time scale and the appearance of additional conformations at room temperature. While well-tempered metadynamics suggests only a modest difference in accessible conformational footprints of the protonated and deprotonated macrocycles, the shift in conformation(s) supports the stabilizing role that the protons adopt in the hydrogen-bonded network.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Org Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Org Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos