Synthesis and cellular characterization of novel isoxazolo- and thiazolohydrazinylidene-chroman-2,4-diones on cancer and non-cancer cell growth and death

Imeri, Faik; Jashri, Ahmed; Bullazhi, Lulzime; Shabani, Agim; Mikhova, Bozhana; Dräger, Gerald; Popovski, Emil; Huwiler, Andrea (2014). Synthesis and cellular characterization of novel isoxazolo- and thiazolohydrazinylidene-chroman-2,4-diones on cancer and non-cancer cell growth and death. Bioorganic & medicinal chemistry, 22(9), pp. 2655-2660. Elsevier 10.1016/j.bmc.2014.03.026

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Coumarins are extensively studied anticoagulants that exert additional effects such as anticancerogenic and even anti-inflammatory. In order to find new drugs with anticancer activities, we report here the synthesis and the structural analysis of new coumarin derivatives which combine the coumarin core and five member heterocycles in hydrazinylidene-chroman-2,4-diones. The derivatives were prepared by derivatization of the appropriate heterocyclic amines which were used as electrophiles to attack the coumarin ring. The structures were characterized by spectroscopic techniques including IR, NMR, 2D-NMR and MS. These derivatives were further characterized especially in terms of a potential cytotoxic and apoptogenic effect in several cancer cell lines including the breast and prostate cancer cell lines MCF-7, MDA-MB-231, PC-3, LNCaP, and the monocytic leukemia cell line U937. Cell viability was determined after 48 h and 72 h of treatment with the novel compounds by MTT assay and the 50% inhibitory concentrations (EC50 values) were determined. Out of the 8 novel compounds screened for reduced cell viability, 4c, 4d and 4e were found to be the most promising and effective ones having EC50 values that were several fold reduced when compared to the reference substance 4-hydroxycoumarin. However, the effects were cancer cell line dependent. The breast cancer MDA-MB-231 cells, the prostate cancer LNCaP cells, and U937 cells were most sensitive, MCF-7 cells were less sensitive, and PC-3 cells were more resistant. Reduced cell viability was accompanied by increased apoptosis as shown by PARP-1 cleavage and reduced activity of the survival protein kinase Akt. In summary, this study has identified three novel coumarin derivatives that in comparison to 4-hydroxycoumarin have a higher efficiency to reduce cancer cell viability and trigger apoptosis and therefore may represent interesting novel drug candidates

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Imeri, Faik and Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0968-0896

Publisher:

Elsevier

Language:

English

Submitter:

Anita Dähler

Date Deposited:

19 Jan 2015 14:38

Last Modified:

11 Nov 2015 10:09

Publisher DOI:

10.1016/j.bmc.2014.03.026

PubMed ID:

24721833

Uncontrolled Keywords:

Chromandiones, Cancer cells, Apoptosis, PARP-1, Akt

BORIS DOI:

10.7892/boris.61993

URI:

https://boris.unibe.ch/id/eprint/61993

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