Influencing Intermolecular Interactions: Exploring the Impact of Charge State on Cyclodextrins and Diverse Bioactive Guests
Várnai Bianka
Gyógyszertudományok és Egészségügyi Technológiák Tagozat
Dr. Zelkó Romána
SE Elméleti Orvostudományi Központ, Hevesy György előadóterem
2024-06-20 10:00:00
Modern Trends in Pharmaceutical Scientific Research
Dr. Antal István
Dr. Béni Szabolcs
Dr. Mirzahosseini Arash
Dr. Fülöp Zoltán
Dr. Tábi Tamás
Dr. Dunkel Petra
Dr. Rusznyák Ágnes
During our experimental work, we aimed at the characterization of the interactions of various cyclodextrins (CD) and bioactive molecules focusing on the role of the charge state of both interacting species by Nuclear Magnetic Resonance (NMR) Spectroscopy. Our work focuses mainly on industrially applied CD-derivatives.
We thoroughly characterized the charge-dependent molecular encapsulation of remdesivir (REM) (Veklury®), using various β- and γCD derivatives (βCD, per6-SBEβCD, SBEβCD, γCD, SBEγCD and sugammadex). The stability constants and the structure of the inclusion complexes were investigated by 1H NMR titration and 2D ROESY NMR experiments. Our investigation revealed that introduction of the anionic sulfobutylether-sidechains on the CD hosts contributes to a significant stability enhancement, furthermore the primary side sulfobutylation of the host plays the most critical role in the stability of the inclusion complex. The pKa value (3.56) of REM was determined experimentally by UV-pH titration for the first time, contributing to the understanding of the molecule’s pH-dependent behaviour.
In our work, we also investigated the complexation of mitragynine (MTR) - the main alkaloid of the kratom plant - with native βCD and its anionic derivative SBEβCD. 1H NMR titrations revealed weak interaction (logβ11 = 0.8; MTR·βCD) between MTR and βCD, whereas a much stronger interaction was determined for SBEβCD (logβ11=3.68, logβ21= 6.87). Our results will be used in the future to investigate different inclusion complexes of structurally related indole and oxindole kratom alkaloids as those are promising skeletons in drug development due to their remarkable opioid-like effects.
In the presented study we characterized intermolecular interactions between the polyanionic, anticoagulant agent fondaparinux (FDPX) and the polycationic per6-NH2-βCD. Stoichiometry and complex stability constants were determined at two different pH values by 1H NMR titrations. Based on 2D ROESY and NOESY NMR experiments outer-sphere, electrostatic-driven complex formulation was determined. The degradation of FDPX under acidic conditions were also investigated. Our NMR and MS results prove that the degradation is manifested by loss of a sulfate group, which appears on the trisulfated GlcNS3S6S subunit, in the form of N-desulfation.
These revelations have great importance, as they aid not only in the development of various drug formulations but also in the large-scale purification, stabilization and chiral analysis of guest molecules within the analytical community. Furthermore, our findings expand the possibilities for the utilization of CDs, presenting them as promising and innovative solutions to address complex challenges associated with drug formulation, stability, purification and chiral analysis.
