Design, synthesis, and evaluation of 4-chromenone derivatives combined with N-acylhydrazone for aurora kinase A inhibitor

Abstract

AbstractThere is accumulating evidence that compounds containing N-acylhydrazone or 4-chromenone moieties can be active against multiple cancer cell types, yet the combined effect of these chemical groups is unclear. This study aimed to develop more effective anti-cancer compounds by combining 4-chromenone and N-acylhydrazone. Thirteen derivatives were designed, synthesized, and characterized, and their structures were identified using nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Most of the derivatives exhibited moderate to high efficacy in inhibiting the clonogenicity of HCT116 colon cancer cells. In particular, derivative 12, (E)-N'-((6-methoxy-4-oxo-4H-chromen-3-yl)methylene)isonicotinohydrazide, strongly inhibited clonogenicity (GI50 = 34.8 μM) of HCT116 cells and aurora kinase A (aurA) activity in vitro (IC50 = 1.4 μM). In silico docking experiment predicted that derivative 12 interacts with aurA based on computational docking and calculations of binding free energy. When derivative 12 was exposed to HCT116 cells, the phosphorylation of aurA at Thr288 was dose-dependently decreased within 60 min. Further analysis showed that derivative 12 destroyed the mitotic spindle in HCT116 cells. These results suggest that derivatives of 4-chromenone combined with N-acylhydrazone are feasible in the development of selective aurA inhibitor and could be considered potential chemotherapeutic agents.