No abstract

Chalcones compounds have been investigated to exhibit anticancer activity through various physiological modes of action. In order to develop chalcone compounds with novel anticancer-related modes of action, diverse chalcone compounds were designed and synthesized. Variously substituted poly-methoxy chalcone compounds 1–17 were prepared, and their structures were identified using high-resolution mass spectrometry (HR/MS) and nuclear magnetic resonance (NMR) experiments. Long-term survival clonogenic assay was applied to evaluate their anti-cancer abilities and revealed that their GI50 values ranged between 1.33 and 172.20 μM. When MCF-7SC cells were treated with various concentrations of compound 14, reduced cell viability and induced apoptosis in MCF-7SC cells were observed in a dose-dependent manner. Wound healing assay demonstrated that compound 14 prevented the MCF7-SC migrated cells at non-lethal concentrations after 12 and 24 h of exposure. The efficiency of compound 14 on the levels of Epithelial-mesenchymal transition (EMT) markers was accessed by the western blot analysis. For the concrete understanding of anticancer properties at the molecular level, in vitro kinase assays on 12 cancer related proteins were carried out. Glycogen synthase kinase 3 beta (GSK3β) was most effectively inhibited by compound 14 with 89% inhibitory activity at 10 µM against GSK3β. The binding mode of compound 14 with GSK3β was reinforced through in silico experiments, which demonstrated compound 14 binds with GSK3β at binding affinity ranged between − 7.5 kcal/mol and − 6.8 kcal/mol. SwissADME analysis provided the druggability and leadlikeness of compound 14, which unveiled drug development possibilities of chalcone compound 14.

The isoflavone compound 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-4H-chromen-4-one (6) was prepared and structurally characterized using NMR, mass spectrum and X-ray crystallography. Compound 6, C18H14O5, was crystallized in the monoclinic space group P21/n with the cell parameters; a = 7.1869(4) Å, b = 10.2764(6) Å, c = 19.6771(10) Å, β = 99.442(2)°, V = 1433.57(14) Å3, Z = 4. In the title compound, the chromenone ring system is slightly twisted from planarity and the dihedral angle formed between the plane of the chromenone ring and benzene ring is 47.75°. Several intermolecular hydrogen bonds make the crystal stabilized in the three-dimensional structure, which was confirmed by Hirshfeld surface analysis. Density functional theory (DFT) calculations at the B3LYP/6-311++G(d,p) level were carried out and the calculated geometric parameters were compared with the experimental results. A frontier molecular orbital calculation was performed to reveal that the energy values of highest occupied molecular orbital (HOMO) and lowest un-occupied molecular orbital (LUMO) were −5.8223 eV and −1.8447 eV, and the HOMO–LUMO energy gap was 3.9783 eV. A clonogenic long-term survival assay of compound 6 against HCT116 human colon cancer cells showed an anti-cancer ability, with GI50 value of 24.9 μM. Docking experiments within the active sites of aurora kinase A and B were carried out to explain the anti-cancer property of compound 6.

There 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.