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Chemoenzymatic Synthesis of Enantiomeric, Bicyclic δ-Halo-γ-lactones with a Cyclohexane Ring, Their Biological Activity and Interaction with Biological Membranes

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Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
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Department of Physics and Biophysics, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
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Laboratory of Microbiology and Plant Biology, Faculty of Natural and Life Sciences, University of Abd El Hamid Ibn Badiss of Mostaganem, Mostaganem 27000, Algeria
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Department of Pharmacology and Toxicology, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375 Wrocław, Poland
5
Central Laboratory of the Instrumental Analysis, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(1), 95; https://doi.org/10.3390/biom10010095
Received: 21 November 2019 / Revised: 24 December 2019 / Accepted: 28 December 2019 / Published: 6 January 2020
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. View Full-Text
Keywords: lactones; halolactonisation; kinetic resolution ofalcohols; antimicrobial activity; antiproliferative activity; hemolytic activity; erythrocytes; biological membranes lactones; halolactonisation; kinetic resolution ofalcohols; antimicrobial activity; antiproliferative activity; hemolytic activity; erythrocytes; biological membranes
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Mazur, M.; Włoch, A.; Bahri, F.; Pruchnik, H.; Pawlak, A.; Obmińska-Mrukowicz, B.; Maciejewska, G.; Gładkowski, W. Chemoenzymatic Synthesis of Enantiomeric, Bicyclic δ-Halo-γ-lactones with a Cyclohexane Ring, Their Biological Activity and Interaction with Biological Membranes. Biomolecules 2020, 10, 95.

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