Synthesis and cellular characterization of novel isoxazolo- and thiazolohydrazinylidene-chroman-2,4-diones on cancer and non-cancer cell growth and death.
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.
Group of Chemistry, Faculty of Natural Sciences & Mathematics, State University of Tetova, 1200 Tetova, Macedonia.
Ahmed
A
Jashari
Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
Faik
F
Imeri
Group of Chemistry, Faculty of Natural Sciences & Mathematics, State University of Tetova, 1200 Tetova, Macedonia; Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
Lulzime
L
Ballazhi
Group of Chemistry, Faculty of Natural Sciences & Mathematics, State University of Tetova, 1200 Tetova, Macedonia.
Agim
A
Shabani
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Build. 9, 1113 Sofia, Bulgaria.
Bozhana
B
Mikhova
Institute of Organic Chemistry, Leibniz Universität Hannover, D-30167 Hannover, Germany.
Gerald
G
Dräger
Institute of Chemistry, Faculty of Natural Sciences & Mathematics, Ss. Cyril & Methodius University, PO Box 162, 1000 Skopje, Macedonia.
Emil
E
Popovski
Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland. Electronic address: Huwiler@pki.unibe.ch.
Andrea
A
Huwiler
D015110:4-Hydroxycoumarins / Q000737:chemistry / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D061986:MCF-7 Cells; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry*; D020298:U937 Cells
D015110:4-Hydroxycoumarins; D000970:Antineoplastic Agents; D003374:Coumarins; D007555:Isoxazoles; D013844:Thiazoles; C030123:coumarin; D011065:Poly(ADP-ribose) Polymerases; C068805:4-hydroxycoumarin
Akt; Apoptosis; Cancer cells; Chromandiones; PARP-1