Acid-Base Equilibrium and Self-Association in Relation to High Antitumor Activity of Selected Unsymmetrical Bisacridines Established by Extensive Chemometric Analysis.

Michał Kosno, Tomasz Laskowski, Joanna E Frackowiak, Agnieszka Potęga, Agnieszka Kurdyn, Witold Andrałojć, Julia Borzyszkowska-Bukowska, Katarzyna Szwarc-Karabyka, Zofia Mazerska

Molecules (Basel, Switzerland) 2022 Jun 21

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Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents previously synthesized by our group. Our recent studies have demonstrated their high antitumor potential against multiple cancer cell lines and human tumor xenografts in nude mice. At the cellular level, these compounds affected 3D cancer spheroid growth and their cellular uptake was selectively modulated by quantum dots. UAs were shown to undergo metabolic transformations in vitro and in tumor cells. However, the physicochemical properties of UAs, which could possibly affect their interactions with molecular targets, remain unknown. Therefore, we selected four highly active UAs for the assessment of physicochemical parameters under various pH conditions. We determined the compounds' pKa dissociation constants as well as their potential to self-associate. Both parameters were determined by detailed and complex chemometric analysis of UV-Vis spectra supported by nuclear magnetic resonance (NMR) spectroscopy. The obtained results indicate that general molecular properties of UAs in aqueous media, including their protonation state, self-association ratio, and solubility, are strongly pH-dependent, particularly in the physiological pH range of 6 to 8. In conclusion, we describe the detailed physicochemical characteristics of UAs, which might contribute to their selectivity towards tumour cells as opposed to their effect on normal cells.

Citation

Michał Kosno, Tomasz Laskowski, Joanna E Frackowiak, Agnieszka Potęga, Agnieszka Kurdyn, Witold Andrałojć, Julia Borzyszkowska-Bukowska, Katarzyna Szwarc-Karabyka, Zofia Mazerska. Acid-Base Equilibrium and Self-Association in Relation to High Antitumor Activity of Selected Unsymmetrical Bisacridines Established by Extensive Chemometric Analysis. Molecules (Basel, Switzerland). 2022 Jun 21;27(13)