Developing novel anticancer agents requires understanding their interactions with biological systems at both the cellular and molecular levels. Enantiomeric lactones have demonstrated notable cytotoxic activities against various cancer cell lines. Building on this foundation, we investigated enantiomeric piperonal-derived trans-β-aryl-δ-iodo-γ-lactones ((-)-(4S,5R,6S) and (+)-(4R,5S,6R)), focusing on their impact on cancer cells membrane (Jurkat and GL-1), model membranes, and biomacromolecules such as human serum albumin (HSA) and DNA. Also, the cytotoxicity toward red blood cells and the antitumor activity of the compounds were evaluated against a set of canine lymphoma and/or leukemia cell lines. Membrane interaction studies revealed that both enantiomers interact with the hydrophobic core of lipid bilayers, enhancing lipid acyl chain packing, with the (-)-(4S,5R,6S) isomer showing a stronger impact on membrane fluidity. Comprehensive spectroscopic and theoretical studies revealed distinct stereochemical differences in binding affinities to HSA, where the (-)-(4S,5R,6S) isomer showed higher binding affinity and significant hydrophobic interactions. Detailed biological studies demonstrated that both enantiomers exhibit antiproliferative and proapoptotic activities, with the (-)-(4S,5R,6S) enantiomer showing higher activity. This study underscores the biological activity and interactions of enantiomeric iodolactones derived from piperonal with biomacromolecules, providing comprehensive insights into their biophysical behavior and potential anticancer properties.

Department of Biophysical Chemistry J Heyrovsky Institute of Physical Chemistry of the Czech Academy of Sciences Dolejskova 3 18223 Prague Czech Republic

Department of Food Chemistry and Biocatalysis Wrocław University of Environmental and Life Sciences Norwida 25 50 375 Wrocław Poland

Department of Pharmacology and Toxicology Wrocław University of Environmental and Life Sciences Norwida 31 50 375 Wrocław Poland

Department of Physics and Biophysics Wrocław University of Environmental and Life Sciences Norwida 25 50 375 Wrocław Poland

Department of Physics and Biophysics Wrocław University of Environmental and Life Sciences Norwida 25 50 375 Wrocław Poland; Department of Biophysical Chemistry J Heyrovsky Institute of Physical Chemistry of the Czech Academy of Sciences Dolejskova 3 18223 Prague Czech Republic

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