Enantiomeric trans β-aryl-δ-iodo-γ-lactones derived from 2,5-dimethylbenzaldehyde induce apoptosis in canine lymphoma cell lines by downregulation of anti-apoptotic Bcl-2 family members Bcl-xL and Bcl-2

Pawlak, Aleksandra; Gładkowski, Witold; Kutkowska, Justyna; Mazur, Marcelina; Obmińska-Mrukowicz, Bożena; Rapak, Andrzej

doi:10.1016/j.bmcl.2018.03.006

Cited by 13 publications

(10 citation statements)

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“…The differences between the enantiomers of bromolactones were significantly higher in comparison with iodolactones. Detailed studies on the antiproliferative effect of enantiomeric trans δ-iodo-γ-lactones with 2,5-dimethylphenyl ring at β position proved a significantly stronger induction of cell death for enantiomer 4 R ,5 S ,6 R [ 25 ] whereas IC 50 values determined in this work for trans δ-bromo-γ-lactones 7 indicated higher potency of enantiomer 4 S, 5 R, 6 S . The same enantiomer of trans δ-iodo-γ-lactone with p -isopropylphenyl substituent at β-position was reported as more active against selected canine cancer cell lines in our previous work [ 34 ].…”

Section: Resultsmentioning

confidence: 82%

“…Exploring the effect of chirality on the activity of tested compounds, we have prepared recently new series of racemic and enantiomerically enriched β-aryl-δ-iodo-γ-lactones with defined configurations of stereogenic centers. Synthesized lactones showed antineoplastic activity against canine cancer lines, namely D17 (canine osteosarcoma), GL-1 (B cell leukemia) and CLBL-1 (B cell lymphoma) [ 23 , 24 ] Furthermore, both enantiomers of trans -δ-iodo-γ-lactones possessing 2,5-dimethylphenyl ring were proved to induce caspase-dependent apoptosis through downregulation of the expression of antiapoptotic proteins Bcl-xL and Bcl-2 [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Preparation of Enantiomeric β-(2′,5′-Dimethylphenyl)Bromolactones, Their Antiproliferative Activity and Effect on Biological Membranes

et al. 2018

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Three novel enantiomeric pairs of bromolactones possesing a 2,5-dimethylphenyl substituent at the β-position of the lactone ring have been synthesized from corresponding enantiomeric (E)-3-(2′,5′-dimethylphenyl)hex-4-enoic acids (4) by kinetically controlled bromolactonization with N-bromosuccinimide (NBS). γ-Bromo-δ-lactones (5) were isolated as the major products. Absolute configurations of stereogenic centers of γ-bromo-δ-lactones (5) were assigned based on X-ray analysis; configurations of cis δ-bromo-γ-lactones (6) and trans δ-bromo-γ-lactones (7) were determined based on mechanism of bromolactonization. Synthesized compounds exhibited significant antiproliferative activity towards the four canine cancer cell lines (D17, CLBL-1, CLB70, and GL-1) and one human cancer line (Jurkat). Classifying the compounds in terms of activity, the most active were enantiomers of trans δ-bromo-γ-lactones (7) followed by enantiomers of cis isomer (6) and enantiomeric γ-bromo-δ-lactones (5). Higher activity was observed for all stereoisomers with S configuration at C-4 in comparison with their enantiomers with 4R configuration. Synthesized compounds did not induce hemolysis of erythrocytes. The results of the interaction of bromolactones with red blood cell membranes suggest that these compounds incorporate into biological membranes, concentrating mainly in the hydrophilic part of the bilayer but have practically no influence on fluidity in the hydrophobic region. The differences in interactions with the membrane between particular enantiomers were observed only for γ-lactones: stronger interactions were found for enantiomer 4R,5R,6S of cis γ-lactone (6) and for enantiomer 4S,5R,6S of trans γ-lactone (7).

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Section: Resultsmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Preparation of Enantiomeric β-(2′,5′-Dimethylphenyl)Bromolactones, Their Antiproliferative Activity and Effect on Biological Membranes

et al. 2018

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“…The antyproliferative activity of lactone enantiomers was tested on two canine cell lines CLB70 and GL-1 ( Table 2). The choice of these specific cell lines was due to the possibility of comparing the results to previous experiments [18][19][20]. All tested substances exhibited significant activity.…”

Section: The Biological Activitymentioning

confidence: 99%

“…In the last few years, our scientific interests have concentrated on the synthesis of biologically active lactones [7,8,16]. In our previous research on antiproliferative compounds, we developed a synthetic pathway to obtain highly active γ-lactones with a β-aryl substituent [17][18][19]. An important element of the structure of these compounds, affecting their activity, was the presence of a halogen atom.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…It was demonstrated that the mechanism of action of the tested enantiomeric trans b-aryl-d-iodo-c-lactones results from the induction of classical caspase-dependent apoptosis as a result of imbalance between the pro-and anti-apoptotic proteins. The study clearly showed a decrease in Bcl-xL and Bcl-2 protein expression in canine lymphoma cell lines under the action of both tested compounds, however, it was demonstrated that (+)-(4R, 5S, 6R)-1 isomer was characterized by higher activity [68]. Taken together, these findings, despite slight differences in individual cell lines, indicated that the enantiomeric trans b-aryl-d-iodo-c-lactones derived from 2,5-dimethylbenzaldehyde act through inducing a decrease in Bcl-2 and Bcl-xL levels, followed by caspase activation and PARP cleavage.…”

Section: Bcl-xl In Canine Cancer Studiesmentioning

confidence: 87%

The Role of Bcl-xL Protein Research in Veterinary Oncology

Pawlak

Henklewska

2020

IJMS

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Due to their significant impact on human and animal health, cancer diseases are an area of considerable concern for both human and veterinary medicine. Research on the cancer pathogenesis in companion animals, such as dogs, allows not only for improving canine cancer treatment, but also for translating the results into human oncology. Disruption of apoptosis in tumor-transformed cells is a well-known mechanism leading to the development of cancer. One of the main factors involved in this process are proteins belonging to the B-cell lymphoma 2 (Bcl-2) family, and the imbalance between pro-apoptotic and anti-apoptotic members of this family contributes to the development of cancer. Studies on the function of these proteins, including B-cell lymphoma-extra large (Bcl-xL), have also been intensively conducted in companion animals. The Bcl-xL gene was sequenced and found to share over 99% homology with the human protein. Research showed that the Bcl-2 family plays the same role in human and canine cells, and data from studies in dogs are fully translatable to other species, including humans. The role of this protein family in cancer development was also confirmed. The article presents the current state of knowledge on the importance of the Bcl-xL protein in veterinary oncology.

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Enantiomeric trans β-aryl-δ-iodo-γ-lactones derived from 2,5-dimethylbenzaldehyde induce apoptosis in canine lymphoma cell lines by downregulation of anti-apoptotic Bcl-2 family members Bcl-xL and Bcl-2

Cited by 13 publications

References 45 publications

Preparation of Enantiomeric β-(2′,5′-Dimethylphenyl)Bromolactones, Their Antiproliferative Activity and Effect on Biological Membranes

Preparation of Enantiomeric β-(2′,5′-Dimethylphenyl)Bromolactones, Their Antiproliferative Activity and Effect on Biological Membranes

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

The Role of Bcl-xL Protein Research in Veterinary Oncology

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