One-dimensional palladium MOF as VEGFR2 and colchicine binding inhibitors with potential anticancer and anti-inflammatory activities: synthesis and molecular investigation

Abstract The innovation of a therapeutic agent with dual anti-inflammatory, anticancer and reversing the dynamic of microtubules like colchicine was crucial. VEGFR2 inhibition has been established as a therapeutic approach for managing cancer, the colchicine site, situated on ß-tubulin and α-tubulin was also considered in cancer development, and metastasis. Moreover, uncontrolled inflammation predisposes to pleiotropic effects leading to cancer development and promoting all stages of tumorigenesis. A polymeric state of a novel one-dimensional palladium-based metal-organic framework (1D Pd-MOF), resulting from the coordination of pyrazine with palladium nuclei to achieve the more pronounced effect of polynuclear characteristics of palladium compared to mononuclear compounds, was designed, synthesized, and screened for its anticancer activity against the A549 lung cancer cell line, with comparison to normal cells. The characterization was performed using different techniques and supported by DFT investigations. The 1D Pd MOF exhibited a potent cytotoxic effect, with an IC 50 value of 78.21 ± 0.41 µg/mL against the A549 lung cancer cell line, while showing minimal toxicity toward the normal WI-38 cell line. To investigate the inhibitory activity of the 1D Pd-MOF towards VEGFR2 kinase and to confirm itseffective molecular target, VEGFR2 kinase inhibition was evaluated. The results demonstrated promising VEGFR2 inhibitory activity with a moderate IC 50 value of 0.658 ± 0.023 µg/mL, compared with an IC 50 value of 0.079 ± 0.003 µg/mL for sorafenib, the reference drug. This activity was further supported by significant inhibition of VEGFR2 gene expression and protein levels compared with untreated control cells. Our results revealed that 1D Pd-MOF is a promising tubulin-interacting compound, as it binds to the colchicine-binding site on tubulin and competes with colchicine in vitro, with an IC 50 value of 3.350 ± 0.21 µg/mL. These findings confirm tubulin as a molecular target of the 1D Pd-MOF and support its observed cytotoxic activity. Furthermore, the 1D Pd-MOF significantly upregulated the expression levels of BAX, P53, and caspase-3 genes, while downregulating CDK4, cyclin D1, and BCL2 genes relative to the control group, suggesting growth inhibition and induction of apoptosis in treated lung carcinoma cells. These findings confirm that the 1D Pd-MOF exerts a clear anticancer effect by triggering programmed cell death through apoptosis. In addition, treatment with the 1D Pd-MOF resulted in substantial accumulation of cells in the sub-G1 fraction, accompanied by a corresponding reduction in the G2/M phase, indicating that its cytotoxic efficacy is primarily mediated through apoptosis induction rather than cell cycle arrest at a specific checkpoint. The anti-inflammatory activity of the 1D Pd-MOF was established by its inhibition of nitric oxide (NO) production in LPS-stimulated RAW cells. Molecular docking studies showed good agreement with the experimental biological findings.