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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 .

Thymic stromal lymphopoietin (TSLP) is a cytokine derived from epithelial cells and plays an essential role in the onset and activation of Th2-derived allergic inflammatory conditions, including atopic dermatitis. Despite their potential as drug targets, well-defined small molecules that effectively block TSLP expression are still lacking. A plant-derived secondary metabolite, aurone, was derivatized based on bioisosteric replacement to identify compounds that inhibit the promoter activity of TSLP. Thirteen (E)-2-benzylidene-1-indanones were designed and synthesized, and their structures were identified using NMR spectroscopy and mass spectrometry. Inhibition of the expression of TSLP triggered by interleukin-4 (IL-4) caused by (E)-2-benzylidene-1-indanones was measured using a TSLP gene promoter-reporter activity assay. Because compound 12, (E)-5-methoxy-2-(3-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one, showed the best activity, further biological experiments, including RT-PCR analysis, quantitative real-time PCR, and inhibitory effects on IL-4-induced early growth response-1 (EGR-1) expression, EGR-1 DNA-binding activity, and IL-4-induced phosphorylation of the mitogen-activated protein kinase (MAPK) signaling cascade were performed. This study demonstrated that compound 12 acts on MAPK to block IL-4-triggered mRNA expression of TSLP via the MAPK-EGR-1 signaling pathway in HaCaT keratinocytes.

The circadian clock system is closely associated with inflammatory responses. Dysregulation of the circadian clock genes in the skin impairs the skin barrier function and affects the pathophysiology of atopic dermatitis. Interleukin 4 (IL-4) is a proinflammatory cytokine derived from T-helper type 2 cells; it plays a critical role in the pathogenesis of atopic dermatitis. Agerarin (6,7-dimethoxy-2,2-dimethyl-2H-chromene) is a natural JAK1/2/3 inhibitor isolated from Ageratum houstonianum that has a protective effect on the epidermal skin barrier. However, it remains unclear whether agerarin affects the circadian clock system. The aim of this study is to investigate the effect of agerarin on IL-4-induced PER2 gene expression in human keratinocytes through reverse transcription (RT)-PCR, quantitative real-time PCR (qPCR), immunoblotting, immunofluorescence microscopic analysis, and real-time bioluminescence analysis. We found that agerarin reduced IL-4-induced PER2 mRNA expression by suppressing the JAK-STAT3 pathway. In addition, real-time bioluminescence analysis in PER2:luc2p promoter-reporter cells revealed that agerarin restored the oscillatory rhythmicity of PER2 promoter activity altered by IL-4. These findings suggest that agerarin may be useful as a cosmeceutical agent against inflammatory skin conditions associated with disrupted circadian rhythms, such as atopic dermatitis.

Matrix metalloproteinase 1 (MMP-1) initiates the breakdown of matrix networks by cleaving fibrillar collagen during the pathophysiological progression of skin aging. Ageratum houstonianum ethanol extract (AHE) has been used as a traditional herbal medicine to treat external wounds and skin diseases. However, the mechanism of action underlying A. houstonianum -mediated modulation of skin aging has not been investigated. In this study, we evaluated the effect of AHE on MMP-1 expression in HaCaT keratinocytes. Gene expression was analyzed by Reverse transcription-PCR (RT-PCR), Quantitative real-time PCR (Q-PCR), gene promoter-reporter assay, and immunoblotting. We found that AHE abrogated TNFα-induced MMP1 expression at the transcriptional level via the suppression of ERK1/2 mitogen-activated protein kinase (MAPK)-mediated Early Growth Response 1 (EGR1) expression. We also demonstrated that β-caryophyllene, a cannabinoid receptor 2 (CB2) agonist, is a functional component of the AHE that inhibits TNFα-induced EGR-1 and MMP1 expression. AHE exerts inhibitory activity on TNFα-induced MMP1 expression at the transcription level through EGR-1 downregulation in keratinocytes. β-Caryophyllene is a bioactive ingredient of AHE that is responsible for the inhibition of TNFα-induced EGR1 expression. β-Caryophyllene can be used as a potential agent to prevent inflammation-induced skin aging.

The juice of Ageratum houstonianum is used in folk medicine as an external wound healing aid for skin injuries. However, the active component of A. houstonianum and its mode of action in skin wound healing has not been investigated. This study was conducted to investigate the effect of A. houstonianum ethanolnolic extract (AHE) on the expression of aquaporin-3 (AQP3), an integral membrane protein for water and glycerol transport in keratinocytes, and to identify the structure of the A. houstonianum bioactive compound. Here, we show that AHE increased AQP3 gene expression at the transcriptional level through the p38 MAPK pathway in HaCaT cells. Furthermore, AHE ameliorated suppression of AQP3 expression caused by ultraviolet B (UVB) irradiation. Agerarin (6,7-dimethoxy-2,2-dimethyl-2 H -chromene) was identified as the bioactive compound responsible for the up-regulation of AQP3 expression by enhancing the expression of the transcription factor circadian locomotor output cycles kaput ( CLOCK ). In conclusion, agerarin is a bioactive compound in AHE responsible for CLOCK-mediated AQP3 expression in keratinocytes.

Targeting cancer stem cell metabolism has emerged as a promising therapeutic strategy for cancer treatment. Breast cancer stem cells (BCSCs) exert distinct metabolism machinery, which plays a major role in radiation and multidrug resistance. Therefore, exploring the mechanisms involved in energy utilization of BCSCs could improve the effectiveness of therapeutic strategies aimed at their elimination. This study was conducted to clarify the glucose metabolism machinery and the function of nootkatone, a bioactive component of grapefruit, in regulating glucose metabolism and stemness characteristics in human breast carcinoma MCF-7 stem cells (MCF-7SCs). In vivo experiments, transcriptomic analysis, seahorse XF analysis, MTT assay, Western blotting, mammosphere formation, wound healing, invasion assay, flow cytometric analysis, reverse transcription-quantitative polymerase chain reaction, and in silico docking experiments were performed. MCF-7SCs showed a greater tumorigenic capacity and distinct gene profile with enrichment of the genes involved in stemness and glycolysis signaling pathways compared to parental MCF-7 cells, indicating that MCF-7SCs use glycolysis rather than oxidative phosphorylation (OXPHOS) for their energy supply. Nootkatone impaired glucose metabolism through AMPK activation and reduced the stemness characteristics of MCF-7SCs. In silico docking analysis demonstrated that nootkatone efficiently bound to the active site of AMPK. Therefore, this study indicates that regulation of glucose metabolism through AMPK activation could be an attractive target for BCSCs.

Chalcones have a skeleton of diphenyls connected via an α,β-unsaturated carbonyl group. Many chalcone derivatives have been shown to interact with tubulin. Based on previous reports, chalcones derived by substitution of a carbonyl group with 2-pyrazoline can be expected to inhibit tubulin polymerization. Therefore, 3,5-diphenyl-2-pyrazolines were prepared to investigate their ability to inhibit tubulin polymerization. The clonogenic long-term survival assay showed that derivative 4, 5-(3,5-dimethoxyphenyl)-3-(2-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide, was the most effective at inhibiting the clonogenicity of HCT116 human colon cancer cells. Derivative 4 induced G2/M cell cycle arrest. In addition, derivative 4 caused dispersed microtubules, a disorganized spherical arrangement of chromosomes, and inhibition of mitotic spindle formation. The binding mode between tubulin and derivative 4 was elucidated by in silico molecular docking. Derivative 4 was superimposed with colchicine and entered the colchicine-binding site well. These results suggest that derivative 4 inhibits tubulin polymerization by binding to the colchicine binding site of tubulin, thus preventing mitotic spindle formation during mitosis in HCT116 colon cancer cells. We propose that derivative 4 could be used as a promising antimitotic chemotherapeutic agent.

We designed 21 ethyl 3,5-diphenyl-2-cyclohexenone-6-carboxylate derivatives to identify compounds exhibiting anticancer activity. To measure the inhibitory effects of the compounds on cancer cell growth, a long-term survival clonogenic assay was performed. Since compounds containing a cyclohexenone moiety inhibit the enzyme acetylcholinesterase, an in vitro acetylcholinesterase assay was performed for all 21 cyclohexenone derivatives. To examine the effect of the derivative that exhibited the best cancer cell growth inhibition on the induction of apoptosis by demonstrating the activation of caspases and apoptosis regulatory proteins, immunoblotting and immunofluorescence microscopic analyses were performed. The binding mode between the cyclohexenone derivatives and acetylcholinesterase was elucidated at the molecular level using in silico docking. Druggability was evaluated based on ligand efficiency.

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-4 H -chromen-3-yl)methylene)isonicotinohydrazide, strongly inhibited clonogenicity (GI 50  = 34.8 μM) of HCT116 cells and aurora kinase A (aurA) activity in vitro (IC 50  = 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.