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Molecules 2016, 21(2), 230;

New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells

Biomedical Science Program, Department of Health Sciences, College of Art and Sciences, Qatar University, Doha 2713, Qatar
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
Department of Analytical and Pharmaceutical Chemistry, Faculty of Pharmacy & Drug Manufacturing, Pharos University, Alexandria, 21311, Egypt
Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21521, Egypt
Department of Biochemistry and Molecular Biology, Howard University, College of Medicine, Washington, DC 20059, USA
Authors to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 3 January 2016 / Revised: 1 February 2016 / Accepted: 1 February 2016 / Published: 18 February 2016
(This article belongs to the Section Medicinal Chemistry)
Full-Text   |   PDF [2422 KB, uploaded 22 February 2016]   |  


The synthesis of new 3-cyano-2-substituted pyridines bearing various pharmacophores and functionalities at position 2 is described. The synthesized compounds were evaluated for their in vitro anti-cancer activities on five cancer cell lines using 5-FU as reference compound. The results revealed that the benzohydrazide derivative 9a induced growth inhibition in human breast cancer cell line MCF-7 with an IC50 value of 2 μM and it showed lower cytotoxicity on MCF-12a normal breast epithelial cells. Additionally, 9a induced apoptotic morphological changes and induced apoptosis in MCF-7 in a dose and time-dependent manner according to an enzyme linked immunosorbent apoptosis assay which is further confirmed by a TUNEL assay. Flow cytometric analysis indicated that 9a arrested MCF-7 cells in the G1 phase, which was further confirmed by increased expression of p21 and p27 and reduced expression of CDK2 and CDK4. Western blot data revealed significant upregulation of the expression of p53, Bax, caspase-3 and down-regulation of Bcl-2, Mdm-2 and Akt. Additionally, 9a increased the release of cytochrome c from mitochondria to cytoplasm which provokes the mitochondrial apoptotic pathway while it showed no significant change on the expression of the death receptor proteins procaspase-8, caspase-8 and FAS. Furthermore, 9a reduced the expression of phospho AKT and β-catenin in dose dependent manner while inhibiting the expression of migration-related genes such as matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF). Our findings suggest that compound 9a could be considered as a lead structure for further development of more potent apoptosis inducing agents with anti-metastatic activities. View Full-Text
Keywords: 3-cyanopyridines; alkoxy substituents; MCF-7; apoptosis; p53; VEGF 3-cyanopyridines; alkoxy substituents; MCF-7; apoptosis; p53; VEGF

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Malki, A.; Mohsen, M.; Aziz, H.; Rizk, O.; Shaban, O.; El-Sayed, M.; Sherif, Z.A.; Ashour, H. New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells. Molecules 2016, 21, 230.

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