Synthesis, in vitro and in silico studies of transition metal complexes of chrysin with potent anticancer activity via GSK3β phosphorylation, modulation of p38 MAPK pathway and HDAC8 inhibition.

The present study involved the synthesis of Cu(II), Fe(II), Co(II), Zn(II) and Ni(II) complexes of chrysin as potential anticancer agents. The metal complexes were extensively characterised via FTIR, NMR, HRMS, elemental analysis, molar conductivity, SEM-EDX and TGA. They were initially screened against HCT116 (colon), CAL51 (breast) and MCF7 (breast) cancer cells. The highest activity was exerted by chrysin's nickel complex (NiC) against HCT116 with an IC50 of 6.88 μM and a 2-fold enhancement in activity relative to chrysin. Moreover, NiC demonstrated lower toxicity towards normal HSF and OEC cells, with ∼5-fold selectivity towards HCT116. Further studies on HCT116 revealed that NiC induced S-phase arrest and necrosis, while Western blotting showed no effect on Bcl2 and caspase-3 expression, confirming the absence of apoptosis. NiC also increased γ-H2AX expression, which is indicative of DNA damage, and resulted in reactive oxygen species (ROS) generation. Furthermore, NiC decreased PTEN expression and increased GSK3β phosphorylation which led to inactivation of its tumour promotion effects. It also modulated p38 MAPK pathway via phosphorylation of tumour suppressors p38 and p53, while no effect was shown on β-catenin. Finally, NiC potently inhibited HDAC8 enzyme with an IC50 of 9.96 μM which was 4-fold more active than chrysin. Overall, NiC caused necrosis via modulation of PTEN/GSK3β pathway, and also via inhibition of HDAC8 resulting in ROS generation, DNA damage, p38/p53 activation and S-phase arrest. DFT calculations, molecular docking and molecular dynamics simulation revealed that NiC possessed higher reactivity and affinity to its receptor with more extensive interactions than chrysin.