PhD Scientific Days 2021

PH_I_L: Pharmaceutical Sciences I. Lectures

Synthesis and Characterization of New Sugammadex-analogue Cyclodextrins

Text of the abstract

Introduction
Cyclodextrins (CDs) are cyclic oligosaccharides, consisting of six (αCD), seven (βCD) or eight (γCD) α-D-glucopyranose units. Owing to their hydrophilic surface and a lipophilic cavity, CDs are able to form inclusion complexes with lipophilic compounds. Due to the moderate aqueous solubility of native CDs, wide range of synthetically modified derivatives are prepared and used for various purposes. Beyond their inclusion complex forming ability, their intrinsic chirality makes CDs an excellent choice as chiral resolving agents in capillary electrophoresis (CE). Sugammadex is a specially designed γCD derivative used as an antidote in the clinical practice, however its analytical applicability has not been explored yet.
Aims
We aimed to synthesize two new sugammadex-analogues, sualphadex and subetadex differing only in their cavity size. Bearing multiple carboxyl moieties, their protonation state determines their interactions with basic compounds, also influencing their inclusion complex formations. Therefore, the characterization of the acid-base properties of these compounds were also intended using NMR spectroscopy. Our third goal was to explore their applicability as chiral selectors in CE.
Methods
The new analogues were synthetized according to Cyclolab Ltd.’s know how. The structures were confirmed by 1H- and 2D NMR and ESI-MS techniques. To determine the pKa values, NMR-pH titration method was used, while the pKa values were calculated using the HypNMR software. CE experiments were performed at pH 7.0, pH 5.0 and pH 2.5 using selected cathinone racemates as test analytes.
Results
The structural identification results supported the single isomeric nature of all compounds, substituted with carboxyethylthio sidechains. Their acid-base properties showed no significant variation, the complete protonation is reached below pH 3, while full disassociation was found above pH 7 in each cases. Accordingly, pH-dependent chiral resolving ability was observed during the CE experiments.
Conclusions: A homologous series of three multianionic CDs were prepared exhibiting similar protonation behavior. Consequently, their divergent interactions with host racemates is only driven by their cavity sizes. For the resolution of the studied cathinones, subetadex turned out to be the most efficient selector, as almost all the 20 selected drugs were successfully resolved.

University and Doctoral School

Semmelweis University, Doctoral School of Pharmaceutical Sciences