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.
Highlights
Initiation and effector mechanisms can be regarded as stages of apoptosis in its simplest model
In vitro human umbilical vein endothelial cells (HUVECs) anti-proliferative assay In order to further assess the antiangiogenic activity of the promising candidates, three compounds (12b, 12c and 13c) showing best VEGFR-2 IC50s were selected to be tested for their ability to in vitro inhibit vascular endothelial growth factor (VEGF)-induced HUVEC cell line proliferation at single dose of 10 mM concentration
Cell-cycle analysis In an attempt to elucidate the potential mechanism of action of the synthesised phthalazines that exhibited potent anti-proliferative activity against the NCI cell panel but weak or moderate VEGFR-2 inhibitory activity, compounds (7b and 16a) were selected to investigate their effect on cell-cycle progression, and induction of apoptosis using breast cancer adenocarcinoma cell line (MCF-7) and colon cancer cell line (HCT-116), respectively
Summary
Cancer is a leading cause of death worldwide. Epidemiological studies revealed that cancer accounts for one of every five deaths. The identification of apoptosis inducers has evolved as an attractive approach for the development of potential anticancer agents From another point of view, angiogenesis, the process of sprouting of new blood vessel formations from pre-existing ones, is regarded as an important hallmark of cancer development. It is currently in clinical trials for gastric and colorectal cancer13 From another point of view, the piperazinyl moiety, the small rigid heterocyclic motif, has been successfully incorporated in several potent kinase inhibitors. A sixth series of substituted piperazine-based derivatives (series F) was prepared as well, via linking the two major fragments: the phthalazine core recognised as a kinase-privileged fragment, to the piperazine moiety aiming to offer more rigidity and to facilitate deriving spatial–activity relationships
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