1. Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition.
- Author
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Elmeligie S, Aboul-Magd AM, Lasheen DS, Ibrahim TM, Abdelghany TM, Khojah SM, and Abouzid KAM
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Death drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Phthalazines chemical synthesis, Phthalazines chemistry, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Vascular Endothelial Growth Factor Receptor-2 metabolism, Antineoplastic Agents pharmacology, Drug Design, Phthalazines pharmacology, Protein Kinase Inhibitors pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds ( 6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a ) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI
50 values ranging from 0.15 to 8.41 µM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas ( 12b, 12c and 13c ) with IC50 s of 4.4, 2.7 and 2.5 μM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 μM, respectively. Additionally, compounds ( 7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.- Published
- 2019
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