Tuning of the Anti-Breast Cancer Activity of Betulinic Acid via Its Conversion to Ionic Liquids
Paula Ossowicz-Rupniewska,
Joanna Klebeko,
Irina Georgieva,
Sonia Apostolova,
Łukasz Struk,
Svetla Todinova,
Rumiana Dimitrova Tzoneva,
Maya Guncheva
Affiliations
Paula Ossowicz-Rupniewska
Department of Chemical Organic Technology and Polymeric Materials, Faculty of Chemical Technology and Engineering, West Pomeranian University of Technology, Piastów Ave. 42, 71-065 Szczecin, Poland
Joanna Klebeko
Department of Chemical Organic Technology and Polymeric Materials, Faculty of Chemical Technology and Engineering, West Pomeranian University of Technology, Piastów Ave. 42, 71-065 Szczecin, Poland
Irina Georgieva
Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 21, 1113 Sofia, Bulgaria
Sonia Apostolova
Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 21, 1113 Sofia, Bulgaria
Łukasz Struk
Department of Organic and Physical Chemistry, Faculty of Chemical Technology and Engineering, West Pomeranian University of Technology, Piastów Ave. 42, 71-065 Szczecin, Poland
Svetla Todinova
Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 21, 1113 Sofia, Bulgaria
Rumiana Dimitrova Tzoneva
Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 21, 1113 Sofia, Bulgaria
Maya Guncheva
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 9, 1113 Sofia, Bulgaria
Betulinic acid (BA) is a natural pentacyclic triterpene with diverse biological activities. However, its low water solubility limits its pharmaceutical application. The conversion of pharmaceutically active molecules into ionic liquids (ILs) is a promising strategy to improve their physicochemical properties, stability, and/or potency. Here, we report the synthesis and characterization of 15 novel ILs containing a cation ethyl ester of a polar, non-polar, or charged amino acid [AAOEt] and an anion BA. Except for [ValOEt][BA], we observed preserved or up to 2-fold enhanced cytotoxicity toward hormone-dependent breast cancer cells MCF-7. The estimated IC50 (72 h) values within the series varied between 4.8 and 25.7 µM. We found that the most cytotoxic IL, [LysOEt][BA]2, reduced clonogenic efficiency to 20% compared to that of BA. In addition, we evaluated the effect of a 72 h treatment with BA or [LysOEt][BA]2, the most cytotoxic compound, on the thermodynamic behavior of MCF-7 cells. Based on our data, we suggest that the charged amino acid lysine included in the novel ILs provokes cytotoxicity by a mechanism involving alteration in membrane lipid organization, which could be accompanied by modulation of the visco–elastic properties of the cytoplasm.
