Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR‐2 Inhibitors

• Published in: Archiv der Pharmazie (Weinheim) Vol. 350; no. 12
• Main Authors: El‐Helby, Abdel‐Ghany A., Ayyad, Rezk R. A., Sakr, Helmy, El‐Adl, Khaled, Ali, Mamdouh M., Khedr, Fathalla
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.12.2017; Wiley Subscription Services, Inc
• Subjects: Anticancer agents; Breast cancer; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Colon; Life Sciences & Biomedicine; Molecular docking; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Triazolo[3,4‐a]phthalazine; VEGFR‐2 inhibitors; VEGFR-2 inhibitors; ASSAY; AMG 900; KINASE INHIBITORS; Anticancer agents; ANTITUMOR-ACTIVITY; CANCER; Molecular docking; ARYLPHTHALAZINES; POTENT; Triazolo[3,4-a]phthalazine; ANTI-ANGIOGENIC THERAPY; RECEPTOR-II; ENDOTHELIAL GROWTH-FACTOR
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201700240

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 IC50 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 IC50 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 IC50 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 IC50 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 IC50 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. Novel series of phthalazine derivatives were designed, synthesized, and evaluated for their anticancer activity against HCT‐116 human colon adenocarcinoma and MCF‐7 breast cancer cells, targeting the VEGFR‐2 enzyme. Compounds 7a,b and 8b,c showed the most promising activities (IC50 (HCT‐116) = 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 µM, respectively) compared to sorafenib as reference drug.