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, Salwa, Aboul-Magd, Asmaa M., Lasheen, Deena S., Ibrahim, Tamer M., Abdelghany, Tamer M., Khojah, Sohair M., and Abouzid, Khaled A. M.
- Subjects
ANTINEOPLASTIC agents ,PHTHALAZINE ,PROTEIN-tyrosine kinases ,CELL death ,CELL cycle ,CHEMICAL 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. [ABSTRACT FROM AUTHOR]- Published
- 2019
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