Uncovering the Potential of Chalcone-Sulfonamide Hybrids: A Systematic Review on Their Anticancer Activity and Mechanisms of Action.

Cancer is the second leading cause of death worldwide and is considered a major public health problem. Despite the significant advances in cancer research, the conventional cancer treatment approaches often lead to serious side effects that affect the quality of life of cancer patients. Thus, searching for new alternatives for cancer treatment is crucial to minimize these problems. Chalcone-sulfonamide hybrids display a range of biological activities and have been widely investigated for their anticancer potential, being considered promising molecules for cancer treatment. This systematic review aimed to summarize the information available in the literature about the anticancer potential of chalcones-sulfonamides in vitro and in vivo and their mechanisms of action. Our analysis demonstrated that chalcones-sulfonamides have relevant cytotoxic potential against different cancer cell lines in vitro, especially against the human colorectal carcinoma cell line HCT-116. These molecules have also reduced tumor growth in vivo. Some chalcones-sulfonamides had improved cytotoxicity after chemical modification and could become more selective or even more potent than reference chemotherapeutics. The mechanisms underlying these effects demonstrated that chalcones-sulfonamides may lead to cell death by different pathways, predominantly via apoptosis or necroptosis. This review may encourage researchers to advance studies with chalcones-sulfonamides, especially to elucidate their mechanisms of action, contributing to the development of new alternatives to cancer treatment.

Modulatory Effects of Chalcone Thio-Derivatives on NF-κB and STAT3 Signaling Pathways in Hepatocellular Carcinoma Cells: A Study on Selected Active Compounds.

Our previous studies demonstrated the modulatory effects of new synthetic thio-chalcone derivatives in dishes on the Nrf2, NF-κB, and STAT3 signaling pathways in colon cancer cells. This study aimed to evaluate the effect of four selected active chalcone thio-derivatives on the NF-κB and STAT3 signaling pathways involved in inflammatory processes and cell proliferation in human liver cancer cells. Cell survival was assessed for cancer (HepG2) and normal (THLE-2) cell lines. Activation of NF-κB and STAT3 signaling pathways and the expression of proteins controlled by these pathways were estimated by Western blot, and qRT-PCR assessed the expression of NF-κB and STAT3 target genes. We also evaluated the impact on the selected kinases responsible for the phosphorylation of the studied transcription factors by MagneticBead-Based Multiplex Immunoassay. Among the thio-derivatives tested, especially derivatives 1 and 5, there was an impact on cell viability, cell cycle, apoptosis, and activation of NF-κB and STAT3 pathways in hepatocellular carcinoma (HCC), which confirms the possibilities of using them in combinatorial molecular targeted therapy of HCC. The tested synthetic thio-chalcones exhibit anticancer activity by initiating proapoptotic processes in HCC while showing low toxicity to non-cancerous cells. These findings confirm the possibility of using chalcone thio-derivatives in molecularly targeted combination therapy for HCC.

Design, synthesis, and antiproliferative activity of new indole/1,2,4-triazole/chalcone hybrids as EGFR and/or c-MET inhibitors.

A novel group of indolyl-1,2,4-triazole-chalcone hybrids was designed, synthesized, and assessed for their anticancer activity. The synthesized compounds exhibited significant antiproliferative activity. Compounds 9a and 9e exhibited significant cancer inhibition with GI50 ranging from 3.69 to 20.40 µM and from 0.29 to >100 µM, respectively. Both compounds displayed a broad spectrum of anticancer activity with selectivity ratios ranging between 0.50-2.78 and 0.25-2.81 at the GI50 level, respectively. The synthesized compounds were also screened for their cytotoxicity by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazol (MTT) assay and for inhibition of epidermal growth factor receptor (EGFR) and c-MET (mesenchymal-epithelial transition factor). Some of the tested compounds exhibited significant inhibition against EGFR and/or c-MET. Compound 9b showed the highest c-MET inhibition (IC50 = 4.70 nM) compared to foretinib (IC50 = 2.5 nM). Compound 9d showed equipotent activity compared with erlotinib against EGFR (IC50 = 0.052 µM) and displayed significant c-MET inhibition with an IC50 value of 4.90 nM.

Design, synthesis, and evaluation of chalcone derivatives as xanthine oxidase inhibitors.

Xanthine oxidase (XO) is an important enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid in the catabolism of purines in humans. This makes XO a well-recognized target in alleviating hyperuricemia. The present study adapted a structure-based drug discovery approach to develop potent and low-toxicity XO inhibitors with the chalcone skeleton. We introduced a carboxyl group and a hydroxyl group to the B ring and modified the A ring. 35 chalcone derivatives were designed and synthesized. All the 35 derivatives exhibited higher XO inhibition activities (IC50 = 0.064-0.559 µM) compared with allopurinol (IC50 = 2.588 µM). Their high affinity was attributed to strong hydrogen bond interactions formed between the introduced carboxyl and hydroxyl groups with key amino acid residues in XO. SAR analysis disclosed that carboxyl, hydroxyl, ethyl (12c), methylamino (12h), dimethylamino (12i), indolin (13k), and indol (13l) groups played important roles in improving the whole molecules' inhibition potency against XO. ADME predictions and cytotoxicity assays suggested their pharmacokinetic characteristics and biocompatibility were desirable. Additionally, 12c exhibited a significant hypouricemic effect on potassium oxonate-induced hyperuricemia rats after orally administrated at a dose range of 10-40 mg/kg, representing a promising anti-hyperuricemia potential for further optimization and development.

Design, synthesis and biological activity of α-nitrile substituted guaiazulene-based chalcone derivatives.

In present study, seventeen α-nitrile substituted guaiazulene-based chalcone derivatives including twelve new were designed, synthesized, and assayed for antiviral, cytotoxicity and signal pathway activities. All derivatives showed potential antiviral activity towards influenza virus or herpes simplex virus (HSV), 7 g with the substitution of nitro group showed strong effects towards H1N1 virus at 30 µM with inhibitory rate of 66.0%, 7o with thiophene exhibited potent anti HSV-1 activities with inhibitory rate of 65.8%. Moreover, several compounds exhibited inhibitory effects on tumor cells and hypoxia-inducible factor-1 (HIF1) signaling pathways. These results showed that α-nitrile substituted guaiazulene-based chalcones offered a promising framework for the further development of new highly efficient drugs.

Design, synthesis and inhibition evaluation of novel chalcone amide α-glucosidase inhibitors.

Aim: The purpose of this study is to design and synthesize a series of novel chalcone amide α-glucosidase (AG) inhibitors (L1-L10) based on virtual screening and molecular dynamics (MD) simulation. Materials & methods: Target compounds (L1-L10) were synthesized from 2-hydroxyacetophenone and methyl 4-formylbenzoate. Results: In vitro activity test shows that most compounds have good AG inhibition. Specially, compound L4 (IC50 = 8.28 ± 0.04 µM) had the best inhibitory activity, superior to positive control acarbose (IC50 = 8.36 ± 0.02 µM). Molecular docking results show that the good potency of L4 maybe attributed to strong interactions between chalcone skeleton and active site, and the torsion of carbon nitrogen bond in amide group. Conclusion: Compound L4 maybe regard as a good anti-Type II diabetes candidate to preform further study.

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Elucidating hydroxysafflor yellow A's multi-target mechanisms against alcoholic liver disease through integrative pharmacology.

BACKGROUND: Alcoholic liver disease (ALD) significantly contributes to global liver-related morbidity and mortality. Natural products play a crucial role in the prevention and treatment of ALD. Hydroxysafflor yellow A (HSYA), a unique and primary component of Safflower (Carthamus tinctorius l.), exhibits diverse pharmacological activities. However, the impact and mechanism of HSYA on ALD have not been fully elucidated. PURPOSE: The purpose of this study was to employ an integrative pharmacology approach to assess the multi-targeted mechanism of HSYA against ALD. METHODS: Network pharmacology and molecular docking techniques were used to analyze the potential therapeutic signaling pathways and targets of HSYA against ALD. An ALD model in zebrafish larvae was established. Larvae were pretreated with HSYA and then exposed to ethanol. Liver injury was measured by fluorescence expression analysis in the liver-specific transgenic zebrafish line Tg (fabp10a:DsRed) and liver tissue H&E staining. Liver steatosis was determined by whole-mount oil red O staining and TG level. Additionally, an ethanol-induced hepatocyte injury model was established in vitro to observe hepatocyte damage (cell viability, ALT level), lipid accumulation (oil red O staining, TC and TG), and oxidative stress (ROS, MDA, GPx and SOD) in HepG2 cells treated with or without HSYA. Finally, qRT-PCR combined with network pharmacology and molecular docking was employed to validate the effects of HSYA on targets. RESULTS: HSYA exhibited a significant, dose-dependent improvement in ethanol-induced liver injury in zebrafish larvae and HepG2 cells. Network pharmacology analysis revealed that HSYA may exert pharmacological effects against ALD through 341 potential targets. These targets are involved in various signaling pathways, including lipid metabolism and atherosclerosis, PI3K-Akt signaling pathway, MAPK signaling pathway, and ALD itself. Molecular docking studies displayed that HSYA had a strong binding affinity toward the domains of IL1B, IL6, TNF, PPARA, PPARG, HMGCR and ADH5. qRT-PCR assays demonstrated that HSYA effectively reversed the ethanol-induced aberrant gene expression of SREBF1, FASN, ACACA, CPT1A, PPARA, IL1B, IL6, TNFα, ADH5, and ALDH2 in vivo and in vitro. CONCLUSION: This study offers a comprehensive investigation into the anti-ALD mechanisms of HSYA using an integrative pharmacology approach. The potential targets of HSYA may be implicated in enhancing ethanol catabolism, reducing lipid accumulation, mitigating oxidative stress, and inhibiting inflammatory response.

Isocoumarins incorporating chalcone moieties act as isoform selective tumor-associated carbonic anhydrase inhibitors.

Aim: A series of isocoumarin-chalcone hybrids were prepared and assays for the inhibition of four isoforms of human carbonic anhydrase (hCA; EC 4.2.1.1), hCA I, II, IX and XII. Materials & methods: Isocoumarin-chalcone hybrids were synthesized by condensing acetyl-isocoumarin with aromatic aldehydes. They did not significantly inhibit off-target cytosolic isoforms hCA I and II (KI >100 µM) but acted as low micromolar or submicromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Results & conclusion: Our work provides insights into a new and scarcely investigated chemotype which provides interesting tumor-associated CA inhibitors, considering that some such derivatives like sulfonamide SLC-0111 are in advanced clinical trials for the management of metastatic advanced solid tumors.

A series of isocoumarin­chalcone hybrids was prepared and assays for the inhibition of four isoforms of the metalloenzyme carbonic anhydrase (CA; EC 4.2.1.1), i.e., human (h) isoforms hCA I, II, IX and XII. Isocoumarins were less investigated as inhibitors of this enzyme. Here we show that the isocoumarin­chalcone hybrids do not significantly inhibit the off-target cytosolic isoforms hCA I and II (K_Is >100 µM) but act as low micromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Our work thus provides insights into a new and scarcely investigated chemotype which may provide interesting tumor-associated CA inhibitors, because some such compounds, e.g., the sulfonamide SLC-0111, are presently in advanced clinical trials for the management of metastatic advanced solid tumors.

Novel coumarin-6-sulfonamide-chalcone hybrids as glutathione transferase P1-1 inhibitors.

Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 µΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.

Synthesis, Anticancer Activity, and Docking Studies of Novel Hydroquinone-Chalcone-Pyrazoline Hybrid Derivatives.

A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone ß-carbon with the furanyl moiety and structural modification of the α,ß-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC50 values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII-X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔGbin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays.

Selective in vitro Synergistic Evaluation of Probiotic Tolerant morpholinyl- and 4-ethylpiperazinyl-Imidazole-chalcone Derivatives on Gastrointestinal System Pathogens.

Imidazole-chalcone compounds are recognised for their broad-spectrum antimicrobial properties. Probiotic-friendly, selective new-generation antimicrobials prove to be more efficient in combating gastrointestinal system pathogens. The aim of this study is to identify imidazole-chalcone derivatives that probiotics tolerate and evaluate their in vitro synergistic antimicrobial effects on pathogens. In this study, fifteen previously identified imidazole-chalcone derivatives were analyzed for their in vitro antimicrobial properties against gastrointestinal microorganisms. Initially, the antimicrobial activity of pathogens was measured using the agar well diffusion method, while the susceptibility of probiotics was determined by microdilution. The chosen imidazole-chalcone derivatives were assessed for synergistic effects using the checkerboard method. Four imidazole-chalcone derivatives to which probiotic bacteria were tolerant exhibited antibacterial and antifungal activity against the human pathogens tested. To our knowledge, this study is the first to reveal the fractional inhibitory concentration (FIC) of combinations of imidazole-chalcone derivatives. Indeed, the minimum inhibitory concentrations (MIC) for morpholinyl- (ZDO-3f) and 4-ethylpiperazinyl- (ZDO-3 m) imidazole-chalcones were notably low when tested against E. coli and B. subtilis, with values of 31.25 µg/mL and 125 µg/mL, respectively. The combination of morpholinyl- and 4-ethylpiperazinyl derivatives demonstrated an indifferent effect against E. coli, but an additive effect was observed for B. subtilis. Additionally, it was observed that imidazole-chalcone derivatives did not exhibit any inhibitory effects on probiotic organisms like Lactobacillus fermentum (CECT-5716), Lactobacillus rhamnosus (GG), and Lactobacillus casei (RSSK-591). This study demonstrates that imidazole-chalcone derivatives that are well tolerated by probiotics can potentially exert a synergistic effect against gastrointestinal system pathogens.

A selective bis-thiophene chalcone-based spectrofluorimetric sensor for Fe3.

A highly selective bis thiophene-based chalcone as a chemosensor for detecting Fe3+ metal ions in DMF: H2O (9:1). This sensor was selective toward ferric ions over other metal ions with a detection limit in micromolar range.

Chalcone-Monoterpene Derivatives from the Buds of Cleistocalyx operculatus and Their Potential as Protein Tyrosine Phosphatase 1B Inhibitors.

Four new compounds, racemic chalcone-monoterpene hybrids (1-3) and a chalcone (9), along with nine known compounds (4-8, 10-13), have been isolated from the buds of Cleistocalyx operculatus. The chemical structures of the isolated compounds were identified through NMR data analysis and confirmed by computational methods, including electronic circular dichroism (ECD) calculations, and further synthetic approaches. Compounds 1-5 were synthesized via a Diels-Alder reaction, a process informed by biomimetic condensation studies that combined chalcones and monoterpenes. These synthetic approaches also yielded various unnatural chalcone-monoterpene derivatives (14-23). The inhibitory effects on protein tyrosine phosphatase 1B (PTP1B) of both naturally isolated and synthetically obtained compounds were evaluated. Compounds 4, 9, 13, and 16b exhibited potent PTP1B inhibitory activity, with IC50 values ranging from 0.9 ± 0.2 to 3.9 ± 0.7 µM. The enantiomers (+)-4 and (-)-16b showed enhanced activity compared to their respective enantiomers. Kinetic studies indicate that all active compounds inhibit PTP1B through mixed mechanisms, and molecular docking simulations agree with the experimental assays on PTP1B. Our results suggest that chalcone-meroterpene adducts from the buds of C. operculatus exhibit potential as antidiabetic agents, partly due to their PTP1B enzyme inhibition.

Absorption enhancement of peach kernel oil on hydroxysafflor yellow A in safflower extracts and its mechanisms.

Carthamus tinctorius L. (Safflower) is extensively used as a functional food and herbal medicine, with its application closely associated with hydroxysafflor yellow A (HSYA). However, the low oral bioavailability of HSYA in safflower extract (SFE) limits its health benefits and application. Our study found that co-administration of 250, 330, and 400 mg/kg peach kernel oil (PKO) increased the oral bioavailability of HSYA in SFE by 1.99-, 2.11-, and 2.49-fold, respectively. The enhanced bioavailability is attributed to improved lipid solubility and intestinal permeability of HSYA in SFE due to PKO. PKO is believed to modify membrane fluidity and tight junctions, increase paracellular penetration, and inhibit the expression and function of P-glycoprotein, enhancing the transcellular transport of substrates. These mechanisms suggest that PKO is an effective absorption enhancer. Our findings provide valuable insights for developing functional foods with improved bioavailability.

Monoterpene-chalcone conjugates and diarylheptanoids isolated from the seeds of Alpinia katsumadai Hayata with cytotoxic activity.

Five undescribed monoterpene-chalcone conjugates (1-5), one undescribed hypothetical precursor of diarylheptanoid (6), two undescribed diarylheptanoids (7-8), and fourteen known compounds (9-22) were isolated from the seeds of Alpinia katsumadai. Their structures were elucidated through the interpretation of HRESIMS, NMR, ECD, and X-ray diffraction data. MTT assays on human cancer cell lines (HepG2, A549, SGC7901, and SW480) revealed that compounds 3-8, 11, and 13 exhibited broad-spectrum antiproliferative activities with IC50 values ranging from 3.59 to 21.78 µM. B cell lymphoma 2 was predicted as the target of sumadain C (11) by network pharmacology and verified by homogeneous time-resolved fluorescence assay and molecular docking.

Sulfonamide-chalcone hybrid compound suppresses cellular adhesion and migration: Experimental and computational insight.

In the present study, the effect of sulfonamide-chalcone 185 (SSC185) was investigated against B16-F10 metastatic melanoma cells aggressive actions, besides migration and adhesion processes, by in silico and in vitro assays. In silico studies were used to characterize the pharmacokinetic profile and possible targets of SSC185, using the pkCSM web server, and docking simulations with AutoDock Tools. Furthermore, the antimetastatic effect of SSC185 was investigated by in vitro experiments using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony, scratch, and cell adhesion assays, and atomic force microscopy (AFM). The molecular docking results show better affinity of SSC185 with the metalloproteinases-2 (MMP-2) and α5ß1 integrin. SSC185 effectively restricts the formation of colonies, migration, and adhesion of B16-F10 metastatic melanoma cells. Through the AFM images changes in cells morphology was identified, with a decrease in the filopodia and increase in the average cellular roughness. The results obtained demonstrate the potential of this molecule in inhibit the primordial steps for metastasis, which is responsible for a worse prognosis of late stage cancer, being the main cause of morbidity among cancer patients.

Chemically Driven Clearance of Amyloid Aggregates by Polyfunctionalized Furo[2,3-b:4,5-b']dipyridine-Chalcone Hybrids to Ameliorate Memory in an Alzheimer Mouse Model.

The aberrant assembly of amyloid-ß (Aß) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aß-targeted immunotherapy reinforce the notion that clearing Aß burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aß aggregates, we synthesized 51 novel polyfunctionalized furo[2,3-b:4,5-b']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-Aß functional assays, Aß aggregation prevention and Aß aggregate clearance, we selected YIAD-0336, (E)-8-((1H-pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2-b]quinolin-9(6H)-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aß directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed Aß plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of Aß aggregates is a promising therapeutic approach for AD.

Chalcone derivatives as promising antifoulants: Molecular optimization, bioactivity evaluation and performance in coatings.

Marine biofouling remains a huge concern for maritime industries and for environmental health. Although the current biocide-based antifouling coatings can prevent marine biofouling, their use has been associated with toxicity for the marine environment, being urgent to find sustainable alternatives. Previously, our research group has identified a prenylated chalcone (1) with promising antifouling activity against the settlement of larvae of the macrofouling species Mytilus galloprovincialis (EC50 = 16.48 µM and LC50 > 200 µM) and lower ecotoxicity when compared to Econea®, a commercial antifouling agent in use. Herein, a series of chalcone 1 analogues were designed and synthesized in order to obtain optimized antifouling compounds with improved potency while maintaining low ecotoxicity. Compounds 8, 15, 24, and 27 showed promising antifouling activity against the settlement of M. galloprovincialis larvae, being dihydrochalcone 27 the most potent. The effect of compound 24 was associated with the inhibition of acetylcholinesterase activity. Among the synthesized compounds, compound 24 also showed potent complementary activity against Navicula sp. (EC50 = 4.86 µM), similarly to the lead chalcone 1 (EC50 = 6.75 µM). Regarding the structure-activity relationship, the overall results demonstrate that the substitution of the chalcone of the lead compound 1 by a dihydrochalcone scaffold resulted in an optimized potency against the settlement of mussel larvae. Marine polyurethane (PU)-based coatings containing the best performed compound concerning anti-settlement activity (dihydrochalcone 27) were prepared, and mussel larvae adherence was reduced compared to control PU coatings.

Significance of Chalcone Scaffolds in Medicinal Chemistry.

Chalcone is a simple naturally occurring α,ß-unsaturated ketone with biological importance, which can also be easily synthesized in laboratories by reaction between two aromatic scaffolds. In plants, chalcones occur as polyphenolic compounds of different frameworks which are bioactive molecules that have been in traditional medicinal practice for many years. Chalcone-based lead molecules have been developed, possessing varied potentials such as antimicrobial, antiviral, anti-inflammatory, anticancer, anti-oxidant, antidiabetic, antihyperurecemic, and anti-ulcer effects. Chalcones contribute considerable fragments to give important heterocyclic molecules with therapeutic utilities targeting various diseases. These characteristic features have made chalcone a topic of interest among researchers and have attracted investigations into this widely applicable structure. This review highlights the extensive exploration carried out on the synthesis, biotransformations, chemical reactions, hybridization, and pharmacological potentials of chalcones, and aims to provide an extensive, thorough, and critical review of their importance, with emphasis on their properties, chemistry, and biomedical applications to boost future investigations into this potential scaffold in medicinal chemistry.

Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds.

BACKGROUND: Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities. AIMS: The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity. METHODS: The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Western Blotting, shRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mice xenograft assay, western blotting. RESULTS: 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R2 = 0.851627) by applying random forest algorithms. The optimal compound J3, which had better activity, concentration-dependently inhibited the formation of gastric cancer cell colonies and led to cell apoptosis by inducing the expression of the pro-apoptotic protein cleaved PARP in a dose-dependent manner. J3 may exert anti-gastric cancer effects by inhibiting the activation of FGFR1/ERK pathway. Moreover, at a dose of 10 mg/kg/day, J3 inhibited tumor growth in nude mice by nearly 70% in vivo with no significant toxic effect on body weight and organs. CONCLUSION: In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug.