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Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR‐2 Inhibitors
Author(s) -
ElHelby AbdelGhany A.,
Ayyad Rezk R. A.,
Sakr Helmy,
ElAdl Khaled,
Ali Mamdouh M.,
Khedr Fathalla
Publication year - 2017
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201700240
Subject(s) - chemistry , sorafenib , phthalazine , docking (animal) , pharmacology , stereochemistry , cancer research , biology , medicine , medicinal chemistry , nursing , hepatocellular carcinoma
Novel series of phthalazine derivatives 6 – 11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT‐116 human colon adenocarcinoma and MCF‐7 breast cancer cells, targeting the VEGFR‐2 enzyme. Compounds 7a , b and 8b , c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC 50 of 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 μM, respectively, and MCF‐7 breast cancer cells with IC 50 of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 μM, respectively, in comparison to sorafenib as reference drug with IC 50 of 5.47 ± 0.3 and 7.26 ± 0.3 μM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR‐2, where compounds 7a , 7b , 8c , and 8b also showed the highest VEGFR‐2 inhibition with IC 50 of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 μM, respectively, in comparison to sorafenib as reference ligand with IC 50 of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR‐2 active site, in order to rationalize their anticancer activity in a qualitative way.