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Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition.


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??M, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10??M, 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.

SUBMITTER: Elmeligie S 

PROVIDER: S-EPMC6691788 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition.

Elmeligie Salwa S   Aboul-Magd Asmaa M AM   Lasheen Deena S DS   Ibrahim Tamer M TM   Abdelghany Tamer M TM   Khojah Sohair M SM   Abouzid Khaled A M KAM  

Journal of enzyme inhibition and medicinal chemistry 20191201 1


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 (<b>6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a</b>) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI<sub>50</sub> values ranging from 0.15 to 8.41 µM. Moreover, the enzymatic assessment of  ...[more]

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