Complexation of daclatasvir by single isomer methylated β-cyclodextrins studied by capillary electrophoresis, NMR spectroscopy and mass spectrometry

Sulaiman Krait; Antonio Salgado; Paola Peluso; Milo Malanga; Tamás Sohajda; Gábor Benkovics; Lukas Naumann; Christian Neusüß; Bezhan Chankvetadze; Gerhard K E Scriba

doi:10.1016/j.carbpol.2021.118486

Complexation of daclatasvir by single isomer methylated β-cyclodextrins studied by capillary electrophoresis, NMR spectroscopy and mass spectrometry

Carbohydr Polym. 2021 Dec 1:273:118486. doi: 10.1016/j.carbpol.2021.118486. Epub 2021 Jul 24.

Authors

Affiliations

¹ Friedrich-Schiller-University Jena, Department of Pharmaceutical/Medicinal Chemistry, Philosophenweg 14, 07743 Jena, Germany.
² University of Alcalá, NMR Spectroscopy Centre (CERMN), CAI Químicas, Faculty of Pharmacy, 28805 Alcalá de Henares, Madrid, Spain.
³ Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Traversa La Crucca, 3 - Regione Baldinca - Li Punti, 07100 Sassari, Italy.
⁴ CycloLab Ltd., Illatos út 7, 1097 Budapest, Hungary.
⁵ Aalen University, Department of Chemistry, Beethovenstrasse 1, 73430 Aalen, Germany.
⁶ Tbilisi State University, Institute of Physical and Analytical Chemistry, School of Exact and Natural Sciences, 0179 Tbilisi, Georgia.
⁷ Friedrich-Schiller-University Jena, Department of Pharmaceutical/Medicinal Chemistry, Philosophenweg 14, 07743 Jena, Germany. Electronic address: gerhard.scriba@uni-jena.de.

PMID: 34560933
DOI: 10.1016/j.carbpol.2021.118486

Abstract

In capillary electrophoresis an enantioseparation of daclatasvir (DCV) was observed in case of heptakis(2,6-di-O-methyl)-β-CD, heptakis(2-O-methyl)-β-CD and β-CD, while two peaks with a plateau were noted for heptakis(2,3,6-tri-O-methyl)-β-CD and heptakis(2,3-di-O-methyl)-β-CD indicating a slow equilibrium. Heptakis(6-O-methyl)-β-CD and heptakis(3-O-methyl)-β-CD yielded broad peaks. Nuclear magnetic resonance experiments including nuclear Overhauser effect-based techniques revealed inclusion complex formation for all CDs with the biphenyl ring of DCV within the cavity and the valine-pyrrolidine moieties protruding from the torus. However, in case of heptakis(2,6-di-O-methyl)-β-CD, heptakis(2-O-methyl)-β-CD and β-CD higher order structures with 1:3 stoichiometry were concluded, where the valine moieties enter additional CD molecules via the secondary side. Heptakis(2,3,6-tri-O-methyl)-β-CD and heptakis(2,3-di-O-methyl)-β-CD yielded primarily 1:1 complexes. Higher order complexes between DCV and heptakis(2,6-di-O-methyl)-β-CD were corroborated by mass spectrometry. Complex stoichiometry was not the reason for the slow equilibrium yielding the plateau observed in capillary electrophoresis, but structural characteristics of the CDs especially complete methylation of the secondary rim.

Keywords: Capillary electrophoresis; Complex stoichiometry; Complex structure; Cyclodextrin-analyte complexation; Mass spectrometry; Nuclear magnetic resonance spectroscopy.