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

• Published in: Chemico-biological interactions Vol. 261; pp. 18 - 26
• Main Authors: Pawlak, Aleksandra, Gładkowski, Witold, Mazur, Marcelina, Henklewska, Marta, Obmińska-Mrukowicz, Bożena, Rapak, Andrzej
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 05.01.2017
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemistry; 4-Butyrolactone - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Canine cancer cell lines; Canine cancers; Caspase 3 - metabolism; Caspase 7 - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Dogs; Enzyme Activation - drug effects; Furans - chemistry; Furans - pharmacology; Lactones - pharmacology; Optical Phenomena; Stereoisomerism; Structure–activity relationship; β-Aryl-δ-iodo-γ-lactones; Canine cancers; Canine cancer cell lines; β-Aryl-δ-iodo-γ-lactones; Structure–activity relationship; Apoptosis
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2016.11.013

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. •Stereoisomers of δ-iodo-γ-lactones induced apoptosis of canine cancer cells.•Observed apoptosis occur via a mitochondrial-mediated, caspase-dependent pathway.•Configuration of stereogenic centers affect anticancer activity of tested lactones.•Activity was higher against canine lymphoma/leukemia than mammary tumor cell lines.