title: Optically active stereoisomers of 5-(1-iodoethyl)-4-(4'-isopropylphenyl)dihydrofuran-2-one: The effect of the configuration of stereocenters on apoptosis induction in canine cancer cell lines.
abstract: Four stereoisomers of δ-iodo-γ-lactones with p-isopropylphenyl substituent at β-position: cis-(4R,5R,6S)-1, cis-(4S,5S,6R)-2, trans-(4R,5S,6R)-3, trans-(4S,5R,6S)-4 with proved antiproliferative activity were subjected to in vitro tests for a better understanding of their anticancer activity. The subject of our interest was a possible relationship between a configuration of chiral centers of the studied lactones and their anticancer potency against a panel of canine cell lines representing hematopoietic (CLBL-1, GL-1, CL-1, CLB70) and mammary gland cancers (P114, CMT-U27, CMT-U309). To determine the anticancer activity of the tested compounds, cell viability and cell metabolic activity were checked using propidium iodide staining and the MTT test. To determine whether the studied compounds cause necrotic or apoptotic cell death, two assays for apoptosis evaluation were performed, annexin V staining and detection of caspase 3/7 activation. Simultaneously, the effects of the compounds on the cell cycle were also examined. The conducted research confirmed the anticancer potential of the tested lactones against canine cancers. The investigated isomers exerted higher activity against canine lymphoma/leukemia cell lines than against mammary tumors, whereas the configuration of stereogenic centers of the examined compounds affected their activity. It has been shown that stereoisomers with 4S configuration (2,4) were more active, and the most potent one was the cis-(4S,5S,6R)-2 isomer. The investigated lactones seemed to initiate the process of apoptosis rather than acting as typical cytostatic agents, as cell death via apoptosis, and no increase in G2-M population in the cell cycle analysis were observed. The presented study demonstrated that all four stereoisomers of δ-iodo-γ-lactones with p-isopropylphenyl substituent at β-position induced apoptosis via a mitochondrial-mediated, caspase-dependent pathway.
authors.affiliation: Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375 Wrocław, Poland. Electronic address: aleksandra.pawlak@up.wroc.pl.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pawlak
authors.affiliation: Department of Chemistry, Faculty of Food Science, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland. Electronic address: glado@poczta.fm.
authors.forename: Witold
authors.initials: W
authors.lastname: Gładkowski
authors.affiliation: Department of Chemistry, Faculty of Food Science, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland. Electronic address: marcelina.mazur@up.wroc.pl.
authors.forename: Marcelina
authors.initials: M
authors.lastname: Mazur
authors.affiliation: Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375 Wrocław, Poland. Electronic address: marta.henklewska@up.wroc.pl.
authors.forename: Marta
authors.initials: M
authors.lastname: Henklewska
authors.affiliation: Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375 Wrocław, Poland. Electronic address: b.mrukowicz@gmail.com.
authors.forename: Bożena
authors.initials: B
authors.lastname: Obmińska-Mrukowicz
authors.affiliation: Laboratory of Tumor Molecular Immunobiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Weigla 12, 53-114 Wroclaw, Poland. Electronic address: rapak@iitd.pan.wroc.pl.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Rapak
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology; D055620:Optical Phenomena; D013237:Stereoisomerism
chemical_list: C000613951:5-(1-iodoethyl)-4-(4'-isopropylphenyl)dihydrofuran-2-one; D005663:Furans; D007783:Lactones; D053148:Caspase 3; D053179:Caspase 7; D015107:4-Butyrolactone
keywords: Apoptosis; Canine cancer cell lines; Canine cancers; Structure–activity relationship; β-Aryl-δ-iodo-γ-lactones