article · Journal of Enzyme Inhibition and Medicinal Chemistry
A series of phthalazine-based chemical compounds was designed and synthesised to evaluate their anti-cancer and anti-angiogenic properties. The molecular designs incorporated biarylamide, biarylurea, or N-substituted piperazine groups attached to the core structure. In laboratory testing across a standard 60-cancer cell panel, eight compounds demonstrated broad-spectrum cytotoxic activity, halting cancer cell growth at low concentrations. Enzymatic assays against VEGFR-2 tyrosine kinase identified three biarylurea derivatives as notable inhibitors that also substantially suppressed the growth of endothelial cells. Further cellular investigations revealed that selected molecules induced cell cycle arrest at the S phase boundary. In particular, one active compound triggered elevated levels of cleaved caspase-3, confirming that it drives tumour cell death through apoptosis. These results indicate the potential of functionalised phthalazines as targeted anti-proliferative agents.
Effective cancer treatment often requires halting tumour cell proliferation while simultaneously restricting the blood vessel formation that nourishes tumours. Targeting VEGFR-2 tyrosine kinase offers a way to interrupt this vessel growth. Identifying synthetic molecules that concurrently impede tumour growth, interrupt the cell cycle, and activate apoptotic cell death provides valuable starting points for designing more targeted oncology treatments.
These compounds serve as early-stage leads for oncology drug discovery. The primary beneficiaries at this stage are pharmaceutical developers and medicinal chemists seeking novel scaffolds for VEGFR-2 inhibition. The research is strictly at an early discovery stage, having demonstrated in vitro activity in cell lines and isolated enzymes. Extensive preclinical safety profiling, pharmacokinetic studies, and in vivo animal testing are necessary before any therapeutic application can emerge.
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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 the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (<b>12b, 12c and 13c</b>) with IC<sub>50</sub>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 (<b>7b, 13c and 16a)</b> were found to induce cell cycle arrest at S phase boundary. Compound <b>7b</b> triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.
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DOI: 10.1080/14756366.2019.1642883
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