Jashari Ahmed, Imeri Faik, Ballazhi Lulzime, Shabani Agim, Mikhova Bozhana, Dräger Gerald, Popovski Emil, Huwiler Andrea
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.
Bioorg Med Chem. 2014 May 1;22(9):2655-61. doi: 10.1016/j.bmc.2014.03.026. Epub 2014 Mar 24.
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.
香豆素是经过广泛研究的抗凝血剂，还具有其他作用，如抗癌甚至抗炎作用。为了寻找具有抗癌活性的新药，我们在此报告新型香豆素衍生物的合成及结构分析，这些衍生物将香豆素核心与肼叉基 - 色满 -2,4 - 二酮中的五元杂环结合在一起。这些衍生物是通过适当的杂环胺衍生化制备的，这些杂环胺用作亲电试剂攻击香豆素环。其结构通过包括红外光谱（IR）、核磁共振（NMR）、二维核磁共振（2D - NMR）和质谱（MS）在内的光谱技术进行表征。这些衍生物进一步进行了表征，特别是在几种癌细胞系中，包括乳腺癌和前列腺癌细胞系MCF - 7、MDA - MB - 231、PC - 3、LNCaP以及单核细胞白血病细胞系U937，评估其潜在的细胞毒性和凋亡诱导作用。在用新型化合物处理48小时和72小时后，通过MTT法测定细胞活力，并确定50%抑制浓度（EC50值）。在筛选的8种具有降低细胞活力作用的新型化合物中，发现4c、4d和4e是最有前景且最有效的，与参考物质4 - 羟基香豆素相比，其EC50值降低了几倍。然而，这些作用依赖于癌细胞系。乳腺癌MDA - MB - 231细胞、前列腺癌LNCaP细胞和U937细胞最敏感，MCF - 7细胞较不敏感，PC - 3细胞更具抗性。如PARP - 1裂解和存活蛋白激酶Akt活性降低所示，细胞活力降低伴随着凋亡增加。总之，本研究鉴定出三种新型香豆素衍生物，与4 - 羟基香豆素相比，它们具有更高的降低癌细胞活力和触发凋亡的效率，因此可能是有趣的新型候选药物。
