Chemoenzymatic Synthesis of Enantiomeric, Bicyclic δ-Halo-γ-lactones with a Cyclohexane Ring, Their Biological Activity and Interaction with Biological Membranes
Marcelina Mazur,
Aleksandra Włoch,
Fouad Bahri,
Hanna Pruchnik,
Aleksandra Pawlak,
Bożena Obmińska-Mrukowicz,
Gabriela Maciejewska,
Witold Gładkowski
Affiliations
Marcelina Mazur
Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
Aleksandra Włoch
Department of Physics and Biophysics, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
Fouad Bahri
Laboratory of Microbiology and Plant Biology, Faculty of Natural and Life Sciences, University of Abd El Hamid Ibn Badiss of Mostaganem, Mostaganem 27000, Algeria
Hanna Pruchnik
Department of Physics and Biophysics, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
Aleksandra Pawlak
Department of Pharmacology and Toxicology, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375 Wrocław, Poland
Bożena Obmińska-Mrukowicz
Department of Pharmacology and Toxicology, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375 Wrocław, Poland
Gabriela Maciejewska
Central Laboratory of the Instrumental Analysis, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
Witold Gładkowski
Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
Starting from 1-acetyl-1-cyclohexene, three enantiomeric pairs (ee ≥ 99%) of bicyclic δ-halo-γ-lactones with cyclohexane ring were obtained in five-step synthesis. The key stereochemical steps were lipase-catalyzed kinetic resolution of racemic 1-(cyclohex-1-en-1-yl) ethanol followed by transfer of chirality to ethyl 2-(2-ethylidenecyclohexyl) acetate in the Johnson−Claisen rearrangement. Synthesized halolactones exhibited antiproliferative activity towards canine B-cell leukemia cells (GL-1) and canine B-cell chronic leukemia cells (CLB70) and the most potent (IC50 18.43 ± 1.46 μg/mL against GL-1, IC50 11.40 ± 0.40 μg/mL against CLB70) comparable with the control etoposide, was (1R,6R,1′S)-1-(1′-chloroethyl)-9-oxabicyclo[4.3.0]nonan-8-one (8b). All halolactones did not have a toxic effect on erythrocytes and did not change the fluidity of membranes in the hydrophobic region of the lipid bilayer. Only weak changes in the hydrophilic area were observed, like the degree of lipid packing and associated hydration. The racemic halolactones were also tested for their antimicrobial properties and found to exhibit selectivity towards bacteria, in particular, towards Proteus mirabilis ATCC 35659.
