Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition
Elmeligie, Salwa; Aboul-Magd, Asmaa M; Lasheen, Deena S.; Ibrahim, Tamer M; Abdelghany, Tamer M; Khojah, Sohair M;
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 GI50 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 IC50s 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.
Other data
Title | Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition | Authors | Elmeligie, Salwa; Aboul-Magd, Asmaa M; Lasheen, Deena S. ; Ibrahim, Tamer M; Abdelghany, Tamer M; Khojah, Sohair M | Keywords | Substituted phthalazines;apoptosis;anti-proliferative;VEGFR-2 kinase inhibitors | Issue Date | Dec-2019 | Publisher | TAYLOR & FRANCIS LTD | Journal | Journal of Enzyme Inhibition and Medicinal Chemistry | Volume | 34 | Issue | 1 | Start page | 1347 | End page | 1367 | ISSN | 1475-6366 | DOI | 10.1080/14756366.2019.1642883 | PubMed ID | 31322015 | Scopus ID | 2-s2.0-85069533149 | Web of science ID | WOS:000476739700001 |
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