European Journal of Chemistry 2016, 7(1), 19-29 | doi: https://doi.org/10.5155/eurjchem.7.1.19-29.1346 | Get rights and content






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Design, synthesis, anticancer evaluation and molecular docking of new V600EBRAF inhibitors derived from pyridopyrazinone


Kamelia Mahmoud Amin (1) , Ossama Metwally El-Badry (2) , Doaa Ezzat Abdel Rahman (3) , Usama Magdi Ammar (4,*) , Mohamed Mostafa Abdalla (5)

(1) Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
(2) Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, 12566, Egypt
(3) Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
(4) Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, 12566, Egypt
(5) Research Unit, Saco Pharma Company, 6th of October City, Egypt
(*) Corresponding Author

Received: 22 Oct 2015 | Revised: 02 Dec 2015 | Accepted: 05 Dec 2015 | Published: 31 Mar 2016 | Issue Date: March 2016

Abstract


Design and synthesis of some new pyridopyrazinone derivatives as anti-proliferative agents is described. The cytotoxic activities of the synthesized compounds against melanoma cell line (LOXIMVI), ovarian cell line (OVCAR3), thyroid cell lines (CAL62, FTC133, BCPAP and ML1) and colon cell lines (HT29 and HCT116) were investigated. Results revealed that most compounds were active and compound 3d was the most active one. It exhibited promising activity against all tested cell lines. In addition, in vitro kinase assay against both WTBRAF and V600EBRAF was performed for all synthesized compounds. Furthermore, molecular docking of tested compounds was established with active site of V600EBRAF kinase domain. Results of kinase inhibition assay and molecular docking revealed that, compounds 1, 3d, e, h, i, 5d, e and 6b were potent inhibitors for V600EBRAF kinase enzyme involved in number of cancer types as melanoma, ovarian and thyroid cancer. The newly synthesized pyridopyrazinones substituted with different substituents at C-3 or fused with triazine heterocycle at C-3 and C-4 afforded potent V600EBRAF inhibitors and exhibited promising cytotoxic activities against different cancer types such as melanoma, ovarian, thyroid and colon cancer.


Keywords


V600EBRAF; Melanoma; Colon cancer; Ovarian cancer; Thyroid cancer; Pyridopyrazinone

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DOI: 10.5155/eurjchem.7.1.19-29.1346

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[1]. Kamelia Amin, Ossama El‐Badry, Doaa Abdel Rahman, Usama Ammar
Synthesis and In Vitro Biological Evaluation of New Pyrido[2,3‐ b ]pyrazinone‐Based Cytotoxic Agents and Molecular Docking as BRAF Inhibitors
ChemistrySelect  4(30), 8882, 2019
DOI: 10.1002/slct.201901487
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[2]. Mohammed S. Abdel-Maksoud, Usama M. Ammar, Chang-Hyun Oh
Anticancer profile of newly synthesized BRAF inhibitors possess 5-(pyrimidin-4-yl)imidazo[2,1-b]thiazole scaffold
Bioorganic & Medicinal Chemistry  27(10), 2041, 2019
DOI: 10.1016/j.bmc.2019.03.062
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[3]. Mohammed S. Abdel-Maksoud, Usama M. Ammar, Mohammed I. El-Gamal, Mahmoud M. Gamal El-Din, Karim I. Mersal, Eslam M.H. Ali, Kyung Ho Yoo, Kyung-Tae Lee, Chang-Hyun Oh
Design, synthesis, and anticancer activity of imidazo[2,1-b]oxazole-based RAF kinase inhibitors
Bioorganic Chemistry  93, 103349, 2019
DOI: 10.1016/j.bioorg.2019.103349
/


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How to cite


Amin, K.; El-Badry, O.; Rahman, D.; Ammar, U.; Abdalla, M. Eur. J. Chem. 2016, 7(1), 19-29. doi:10.5155/eurjchem.7.1.19-29.1346
Amin, K.; El-Badry, O.; Rahman, D.; Ammar, U.; Abdalla, M. Design, synthesis, anticancer evaluation and molecular docking of new V600EBRAF inhibitors derived from pyridopyrazinone. Eur. J. Chem. 2016, 7(1), 19-29. doi:10.5155/eurjchem.7.1.19-29.1346
Amin, K., El-Badry, O., Rahman, D., Ammar, U., & Abdalla, M. (2016). Design, synthesis, anticancer evaluation and molecular docking of new V600EBRAF inhibitors derived from pyridopyrazinone. European Journal of Chemistry, 7(1), 19-29. doi:10.5155/eurjchem.7.1.19-29.1346
Amin, Kamelia, Ossama Metwally El-Badry, Doaa Ezzat Abdel Rahman, Usama Magdi Ammar, & Mohamed Mostafa Abdalla. "Design, synthesis, anticancer evaluation and molecular docking of new V600EBRAF inhibitors derived from pyridopyrazinone." European Journal of Chemistry [Online], 7.1 (2016): 19-29. Web. 28 Feb. 2020
Amin, Kamelia, El-Badry, Ossama, Rahman, Doaa, Ammar, Usama, AND Abdalla, Mohamed. "Design, synthesis, anticancer evaluation and molecular docking of new V600EBRAF inhibitors derived from pyridopyrazinone" European Journal of Chemistry [Online], Volume 7 Number 1 (31 March 2016)

DOI Link: https://doi.org/10.5155/eurjchem.7.1.19-29.1346

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