Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents.

This study presents the synthesis of four series of novel hybrid chalcones (20,21)a-g and (23,24)a-g and six series of 1,3,5-triazine-based pyrimido[4,5-b][1,4]diazepines (28-33)a-g and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones 20b,d, 21a,b,d, 23a,d-g, 24a-g and the pyrimido[4,5-b][1,4]diazepines 29e,g, 30g, 31a,b,e-g, 33a,b,e-g exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI50 values between 0.01 and 100 µM and LC50 values in the range of 4.09 µM to >100 µM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against N. gonorrhoeae, S. aureus (ATCC 43300), and M. tuberculosis were exhibited by the pyrimido[4,5-b][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone 29e and triazinyloxy-chalcone 31g were the most active compounds against T. rubrum and T. mentagrophytes and A. fumigatus, respectively (MICs = 62.5 µg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.

Flavokawain C inhibits proliferation and migration of liver cancer cells through FAK/PI3K/AKT signaling pathway.

PURPOSE: This study investigated the potential applicability and the underlying mechanisms of flavokawain C, a natural compound derived from kava extracts, in liver cancer treatment. METHODS: Drug distribution experiment used to demonstrate the preferential tissues enrichment of flavokawain C. Cell proliferation, apoptosis and migration effect of flavokawain C were determined by MTT, colony formation, EdU staining, cell adhesion, transwell, flow cytometry and western blot assay. The mechanism was explored by comet assay, immunofluorescence assay, RNA-seq-based Kyoto encyclopedia of genes and genomes analysis, molecular dynamics, bioinformatics analysis and western blot assay. The anticancer effect of flavokawain C was further confirmed by xenograft tumor model. RESULTS: The studies first demonstrated the preferential enrichment of flavokawain C within liver tissues in vivo. The findings demonstrated that flavokawain C significantly inhibited proliferation and migration of liver cancer cells, induced cellular apoptosis, and triggered intense DNA damage along with strong DNA damage response. The findings from RNA-seq-based KEGG analysis, molecular dynamics, bioinformatics analysis, and western blot assay mechanistically indicated that treatment with flavokawain C notably suppressed the FAK/PI3K/AKT signaling pathway in liver cancer cells. This effect was attributed to the induction of gene changes and the binding of flavokawain C to the ATP sites of FAK and PI3K, resulting in the inhibition of their phosphorylation. Additionally, flavokawain C also displayed the strong capacity to inhibit Huh-7-derived xenograft tumor growth in mice with minimal adverse effects. CONCLUSIONS: These findings identified that flavokawain C is a promising anticancer agent for liver cancer treatment.

Probing the inhibition of MAO-B by chalcones: an integrated approach combining molecular docking, ADME analysis, MD simulation, and MM-PBSA calculations.

CONTEXT: Monoamine oxidase B (MAO-B), an enzyme of significant relevance in the realm of neurodegenerative disorders, has garnered considerable attention as a potential target for therapeutic intervention. Natural compounds known as chalcones have shown potential as MAO-B inhibitors. In this particular study, we employed a multimodal computational method to evaluate the inhibitory effects of chalcones on MAO-B. METHODS: Molecular docking methods were used to study and assess the complicated binding interactions that occur between chalcones and MAO-B. This extensive analysis provided a valuable and deep understanding of possible binding methods as well as the key residues implicated in the inhibition process. Furthermore, the ADME investigation gave valuable insights into the pharmacokinetic properties of chalcones. This allowed them to be assessed in terms of drug-like attributes. The use of MD simulations has benefited in the research of ligand-protein interactions' dynamic behaviour and temporal stability. MM-PBSA calculations were also done to estimate the binding free energies and acquire a better knowledge and understanding of the binding affinity between chalcones and MAO-B. Our thorough method gives a thorough knowledge of chalcones' potential as MAO-B inhibitors, which will be useful for future experimental validation and drug development efforts in the context of neurodegenerative illnesses.

Novel furan chalcone modulates PHD-2 induction to impart antineoplastic effect in mammary gland carcinoma.

Normoxic inactivation of prolyl hydroxylase-2 (PHD-2) in tumour microenvironment paves the way for cancer cells to thrive under the influence of HIF-1α and NF-κB. Henceforth, the present study is aimed to identify small molecule activators of PHD-2. A virtual screening was conducted on a library consisting of 265,242 chemical compounds, with the objective of identifying molecules that exhibit structural similarities to the furan chalcone scaffold. Further, PHD-2 activation potential of screened compound was determined using in vitro 2-oxoglutarate assay. The cytotoxic activity and apoptotic potential of screened compound was determined using various staining techniques, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, 4',6-diamidino-2-phenylindole (DAPI), 1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1), and acridine orange/ethidium bromide (AO/EB), against MCF-7 cells. 7,12-Dimethylbenz[a]anthracene (DMBA) model of mammary gland cancer was used to study the in vivo antineoplastic efficacy of screened compound. [(E)-1-(4-fluorophenyl)-3-(furan-2-yl) prop-2-en-1-one] (BBAP-7) was screened and validated as a PHD-2 activator by an in vitro 2-oxo-glutarate assay. The IC50 of BBAP-7 on MCF-7 cells is 18.84 µM. AO/EB and DAPI staining showed nuclear fragmentation, blebbing and condensation in MCF-7 cells following BBAP-7 treatment. The red-to-green intensity ratio of JC-1 stained MCF-7 cells decreased after BBAP-7 treatment, indicating mitochondrial-mediated apoptosis. DMBA caused mammary gland dysplasia, duct hyperplasia and ductal carcinoma in situ. Carmine staining, histopathology, and scanning electron microscopy demonstrated that BBAP-7, alone or with tirapazamine, restored mammary gland surface morphology and structural integrity. Additionally, BBAP-7 therapy significantly reduced oxidative stress and glycolysis. The findings reveal that BBAP-7 activates PHD-2, making it a promising anticancer drug.

Design, Synthesis, and Molecular Docking of Novel Miscellaneous Chalcones as p38α Mitogen-Activated Protein Kinase Inhibitors.

New chalcones were synthesized and evaluated to serve as p38-α type of mitogen-activated protein kinase (MAPK) inhibitors. According to the National Cancer Institute, the findings indicated that at a 10 µM dosage, compounds 3a and 6 were the most active among all the compounds examined, with mean growth inhibition% of 94.83 and 58.49, respectively. In 5-dose testing, they showed anticancer activity in the micro-molar range with GI50 in the range of 1.41-46.1 and 2.07-31.3 µM, respectively. Besides, powerful activity, especially against the leukaemia cell lines and good selectivity to cancer cells compared to normal PCS-800-017 with a selectivity index=12.41 and 23.77, respectively. Compounds 3a and 6 inhibited p38α MAPK with IC50 values of 0.1462±0.0063 and 0.4356±0.0189 µM, correspondingly. 3a showed good inhibition for HL-60(TB) cells and induced cell cycle arrest in HL-60(TB) cells at the G2/M phase. Besides, it elevated the total apoptosis by 14.68-fold and increased the caspase-3 level by 3.52-fold compared with doxorubicin, which raised it by 4.30-fold, inducing apoptosis by acting as caspase-dependent inducers. These results suggest that 3a is a promising antiproliferative and p38α MAPK inhibitor, confirmed by molecular docking with high compatibility 3a with the p38α MAPK binding site.

Synergistic Antibacterial Activity of Gallic Acid Based Chalcone Indl 2 by Inhibiting Efflux Pump Transporters.

As a part of novel discovery of drugs from natural resources, present study was undertaken to explore the antibacterial potential of chalcone Indl-2 in combination with different group of antibiotics. MIC of antibiotics was reduced up to eight folds against the different cultures of E. coli by both chalcones. Among the two compounds, the i. e. 1-(3', 4,'5'-trimethoxyphenyl)-3-(3-Indyl)-prop-2-enone (6, Indl-2), a chalcone derivative of gallic acid (Indl-2) was better along with tetracycline (TET) worked synergistically and was found to inhibit efflux transporters as obvious by ethidium bromide efflux confirmed by ATPase assays and docking studies. In combination, Indl-2 kills the MDREC-KG4 cells, post-antibiotic effect (PAE) of TET was prolonged and mutant prevention concentration (MPC) of TET was also decreased. In-vivo studies revealed that Indl-2 reduces the concentration of TNF-α. In acute oral toxicity study, Indl-2 was non-toxic and well tolerated up-to dose of 2000 mg/kg. Perhaps, the study is going to report gallic acid derived chalcone as synergistic agent acting via inhibiting the primary efflux pumps.

Synthesis and Evaluation of New Phytotoxic Fluorinated Chalcones as Photosystem II and Seedling Growth Inhibitors.

The development of novel phytotoxic compounds has been an important aim of weed control research. In this study, we synthesized fluorinated chalcone derivatives featuring both electron-donating and electron-withdrawing groups. These compounds were evaluated both as inhibitors of the photosystem II (PSII) electron chain as well as inhibitors of the germination and seedling growth of Amaranthus plants. Chlorophyll a (Chl a) fluorescence assay was employed to evaluate their effects on PSII, while germination experiments were conducted to assess their impact on germination and seedling development. The results revealed promising herbicidal activity for (E)-3-(4-bromophenyl)-1-(4-fluorophenyl)prop-2-en-1-one (7 a) and (E)-1-(4-fluorophenyl)-3-phenylprop-2-en-1-one (7 e). Compounds 7 a and 7 e exhibited a reduction in Chl a parameters associated with performance indexes and electron transport per reaction center. This reduction suggests a decrease in PSII activity, attributed to the blockage of electron flow at the quinone pool. Molecular docking analyses of chalcone derivatives with the D1 protein of PSII revealed a stable binding conformation, wherein the carbonyl and fluorine groups interacted with Phe265 and His215 residues, respectively. Additionally, at a concentration of 100 µM, compound 7 e demonstrated pre- and post-emergent herbicidal activity, resulting in a reduction of the seed germination index, radicle and hypocotyl lengths of Amaranthus weeds.

Furan-based Chalcone Annihilates the Multi-Drug-Resistant Pseudomonas aeruginosa and Protects Zebra Fish Against its Infection.

The emergence of carbapenem-resistant Pseudomonas aeruginosa, a multi-drug-resistant bacteria, is becoming a serious public health concern. This bacterium infects immunocompromised patients and has a high fatality rate. Both naturally and synthetically produced chalcones are known to have a wide array of biological activities. The antibacterial properties of synthetically produced chalcone were studied against P. aeruginosa. In vitro, study of the compound (chalcone derivative named DKO1), also known as (2E)-1-(5-methylfuran-2-yl)-3-(4-nitrophenyl) prop-2-en-1-one, had substantial antibacterial and biofilm disruptive action. DKO1 effectively shielded against P. aeruginosa-induced inflammation, oxidative stress, lipid peroxidation, and apoptosis in zebrafish larvae. In adult zebrafish, the treatment enhanced the chances of survivability and reduced the sickness-like behaviors. Gene expression, biochemical analysis, and histopathology studies found that proinflammatory cytokines (TNF-α, IL-1ß, IL-6, iNOS) were down regulated; antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) levels increased, and histoarchitecture was restored in zebrafish. The data indicate that DKO1 is an effective antibacterial agent against P. aeruginosa demonstrated both in vitro and in vivo.

Synthesis, Characterization, Antioxidant, and Anticancer Activity against Colon Cancer Cells of Some Cinnamaldehyde-Based Chalcone Derivatives.

The purpose of the current investigation was to produce cinammaldehyde-based chalcone derivatives (3a-k) to evaluate their potential effectiveness as antioxidant and inhibitory agents versus human Caco-2 cancer cells. The findings obtained using the DPPH assay showed that compound 3e had the highest effective antioxidant activity with the best IC50 value compared with the other compounds. Moreover, the cytotoxic findings revealed that compound 3e was the best compound for inhibiting Caco-2 development in contrast to all other produced derivatives, with the lowest IC50 concentration (32.19 ± 3.92 µM), and it also had no detrimental effects on healthy human lung cells (wi38 cells). Exposure of Caco-2 cells with this IC50 value of compound 3e resulted in a substantial rise in the number of early and late cells that are apoptotic with a significant comet nucleus when compared with control cells employing the annexin V/PI and comet evaluations, respectively. Furthermore, qRT-PCR and ELISA examinations indicated that compound 3e significantly altered the expression of genes and their relative proteins related to apoptosis in the treated Caco-2 cells, thus significantly inhibiting Caco-2 growth through activating Caspase-3 via an intrinsic apoptotic pathway. As a result, compound 3e could serve as an effective therapy for human colon cancer.

2'-Hydroxychalcone Induces Autophagy and Apoptosis in Breast Cancer Cells via the Inhibition of the NF-κB Signaling Pathway: In Vitro and In Vivo Studies.

2'-Hydroxychalcone is a hydroxyl derivative of chalcones, which are biosynthetic precursors of flavonoids and rich in the human diet. The anticancer activity of 2'-hydroxychalcone has been reported in several cancers but remains to be investigated in breast cancer. In the current study, 2'-hydroxychalcone showed significant cytotoxicity against breast cancer cell lines MCF-7 and CMT-1211. It could inhibit breast cancer cell proliferation, migration, and invasion in vitro and suppress tumor growth and metastasis in vivo. Mechanistic investigation revealed that the NF-κB pathway was significantly inhibited by 2'-hydroxychalcone treatment accompanied by an excessive intracellular accumulation of reactive oxygen species, induction of endoplasmic reticulum stress, and activation of JNK/MAPK. In addition, 2'-hydroxychalcone elevated the autophagic levels in breast cancer cells equipped with increasing numbers of autophagy vesicles and complete autophagic flux. Finally, autophagy-dependent apoptosis was observed in 2'-hydroxychalcone-induced cell death. In conclusion, 2'-hydroxychalcone enhances the autophagic levels and induces apoptosis in breast cancer cells, which could be contributed to the inhibition of the pro-survival NF-κB signaling, indicating a promising potential for 2'-hydroxychalcone in future anticancer drug development.

Methoxychalcones as potential anticancer agents for colon cancer: Is membrane perturbing potency relevant?

Chalcones are naturally produced by many plants, and constitute precursors for the synthesis of flavons and flavanons. They were shown to possess antibacterial, antifungal, anti-cancer, and anti- inflammatory properties. The goal of the study was to assess the suitability of three synthetic methoxychalcones as potential anticancer agents. In a panel of colon cancer cell lines they were demonstrated to be cytotoxic, proapoptotic, causing cell cycle arrest, and increasing intracellular level of reactive oxygen species. Anticancer activity of the compounds was not diminished in the presence of stool extract containing microbial enzymes that could change the structure of chalcones. Moreover, methoxychalcones interacted strongly with model phosphatidylcholine membranes as detected by differential scanning calorimetry. Metohoxychalcones particularly affected the properties of lipid domains in giant unilamellar liposomes formed from raft-mimicking lipid composition. This may be of importance since many molecular targets for therapy of metastatic colon cancer are raft-associated receptors (e.g., receptor tyrosine kinases). The importance of membrane perturbing potency of methoxychalcones for their biological activity was additionally corroborated by the results obtained by molecular modelling.

Isobavachalcone attenuates liver fibrosis via activation of the Nrf2/HO-1 pathway in rats.

Liver fibrosis, a progression of chronic liver disease, is a significant concern worldwide due to the lack of effective treatment modalities. Recent studies have shown that natural products play a crucial role in preventing and treating liver fibrosis. Isobavachalcone (IBC) is a chalcone compound with anti-inflammatory, antioxidant, and anti-cancer properties. However, its potential antifibrotic effects remain to be elucidated. This study aimed to investigate the antifibrotic effects of IBC on liver fibrosis and its underlying mechanisms in rats. The results showed that IBC significantly ameliorated the pathological damage and collagen deposition in liver tissues; it also reduced the levels of hydroxyproline (HYP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). In addition, IBC activated Nuclear factor E2-associated factor 2/Hemeoxygenase-1 (Nrf2/HO-1) signaling, leading to the nuclear translocation of Nrf2. This translocation subsequently increased the levels of superoxide dismutase (SOD) and glutathione (GSH) and decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), thereby alleviating oxidative stress-induced damage. Moreover, it inhibited the expression of nuclear factor kappa B (NF-κB), which further reduced the levels of downstream inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 beta (IL-1ß), thereby suppressing the activation of HSCs and weakening liver fibrosis. In HSC-T6 cell experiments, changes observed in inflammatory responses, oxidative stress indicators, and protein expression were consistent with the in vivo results. Furthermore, the Nrf2 inhibitor (ML385) attenuated the effect of IBC on inhibiting the activation of quiescent HSCs. Consequently, IBC could alleviate liver fibrosis by activating Nrf2/ HO-1 signaling.

Dinuclear copper(II) complexes with a bridging bis(chalcone) ligand reveal considerable in vitro cytotoxicity on human cancer cells and enhanced selectivity.

A bis(chalcone) molecule (H2L) was synthesized via Aldol's condensation from terephthalaldehyde and 2'-hydroxyacetophenone and it was used as bridging ligand for the preparation of five dinuclear copper(II) complexes of the composition [Cu(NN)(µ-L)Cu(NN)](NO3)2⋅nH2O (n = 0-2) (1-5), where NN stands for a bidentate N-donor ligand such as phen (1,10-phenanthroline, 1), bpy (2,2'-bipyridine, 2), mebpy (5,5'-dimethyl-2,2'-dipyridine, 3), bphen (bathophenanthroline, 4) and nphen (5-nitro-1,10-phenanthroline, 5). The compounds were characterized by different suitable techniques to confirm their purity, composition, and structure. Moreover, the products were evaluated for their in vitro cytotoxicity on a panel of human cancer cell lines: ovarian (A2780), ovarian resistant to cisplatin (A2780R), prostate (PC3), osteosarcoma (HOS), breast (MCF7) and lung (A549), and normal fibroblasts (MRC-5), showing significant cytotoxicity in most cases, with IC50 ≈ 0.35-7.8 µM. Additionally, the time-dependent cytotoxicity and cellular uptake of copper, together with flow cytometric studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production in A2780 cells, were also performed. The results of biological testing on A2780 cells pointed out a possible mechanism of action characterized by the G2/M cell cycle arrest and induction of apoptosis by triggering the intrinsic signalling pathway associated with the damage of mitochondrial structure and depletion of mitochondrial membrane potential. SYNOPSIS: Dinuclear Cu(II) complexes bearing a bridging bis(chalcone) ligand revealed high in vitro cytotoxicity, initiated A2780 cell arrest at G2/M phase and efficiently triggered intrinsic pathway of apoptosis.

Two Prenylated Chalcones, 4-Hydroxyderricin, and Xanthoangelol Prevent Postprandial Hyperglycemia by Promoting GLUT4 Translocation via the LKB1/AMPK Signaling Pathway in Skeletal Muscle Cells.

SCOPE: Stimulation of glucose uptake in the skeletal muscle is crucial for the prevention of postprandial hyperglycemia. Insulin and certain polyphenols enhance glucose uptake through the translocation of glucose transporter 4 (GLUT4) in the skeletal muscle. The previous study reports that prenylated chalcones, 4-hydroxyderricin (4-HD), and xanthoangelol (XAG) promote glucose uptake and GLUT4 translocation in L6 myotubes, but their underlying molecular mechanism remains unclear. This study investigates the mechanism in L6 myotubes and confirms antihyperglycemia by 4-HD and XAG. METHODS AND RESULTS: In L6 myotubes, 4-HD and XAG promote glucose uptake and GLUT4 translocation through the activation of adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B1 (LKB1) signaling pathway without activating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and Janus kinases (JAKs)/signal transducers and activators of transcriptions (STATs) pathways. Moreover, Compound C, an AMPK-specific inhibitor, as well as siRNA targeting AMPK and LKB1 completely canceled 4-HD and XAG-increased glucose uptake. Consistently, oral administration of 4-HD and XAG to male ICR mice suppresses acute hyperglycemia in an oral glucose tolerance test. CONCLUSION: In conclusion, LKB1/AMPK pathway and subsequent GLUT4 translocation in skeletal muscle cells are involved in Ashitaba chalcone-suppressed acute hyperglycemia.

Novel GSH-responsive prodrugs derived from indole-chalcone and camptothecin trigger apoptosis and autophagy in colon cancer.

Antineoplastic agents that target tubulin have shown efficacy as chemotherapeutic drugs, yet they are often constrained by multidrug resistance (MDR) and unwanted side effects. A multi-targeted strategy demonstrates great potency in reducing toxicity and enhancing efficacy and provides an alternative way for attenuating MDR. In this study, a series of dual-targeted anti-cancer agents based on indole-chalcone derivatives and the camptothecin (CPT) scaffold were synthesized. Among them, 14-1 demonstrated superior anti-proliferative activity than its precursor 13-1, CPT or their physical mixtures against tested cancer cells, including multidrug-resistant variants, while exhibited moderate cytotoxicity toward human normal cells. Mechanistic studies revealed that 14-1 acted as a glutathione-responsive prodrug, inducing apoptosis by substantially enhancing intracellular uptake of CPT, inhibiting tubulin polymerization, increasing the accumulation of intracellular reactive oxygen species, and initiating a mitochondrion-dependent apoptotic pathway. Moreover, 14-1 notably induced autophagy and suppressed topoisomerase I activity to further promote apoptosis. Importantly, 14-1 displayed potent inhibitory effect on tumor growth in paclitaxel (PTX)-resistant colorectal cancer (HCT-116/PTX) xenograft models without inducing obvious toxicity compared with CPT- or combo-treated group. These results suggest that 14-1 holds promise as a novel candidate for anti-cancer therapy, particularly in PTX-resistant cancers.

Cardamonin decreases inflammatory mediator expression in IL-1ß-stimulated human periodontal ligament cells.

BACKGROUND: Cardamonin is classified as a natural chalcone, and has been reported to possess various bioactive effects. However, there have been limited attempts to utilize cardamonin in the treatment of periodontitis. This study aimed to investigate whether cardamonin has anti-inflammatory effects on human periodontal ligament cells (HPDLCs), which are a component cell of periodontal tissue. Specifically, the study seeks to determine whether cardamonin affects the expression of inflammatory mediators, such as cytokines and adhesion molecules, induced by interleukin-1ß (IL-1ß) in HPDLCs, as well as the signaling pathways activated by IL-1ß. METHODS: Cytokine and chemokine levels in supernatants of HPDLCs were measured by ELISA. Western blot analysis was used to measure protein expression and signal transduction pathway activation in HPDLCs. RESULTS: We found that IL-1ß-induced CC chemokine ligand (CCL)2, CCL5, CCL20, CXC-chemokine ligand (CXCL)10, and interleukin (IL)-6 production and intercellular adhesion molecule (ICAM)-1 and cyclooxygenase (COX)-2 expression in HPDLCs were suppressed by cardamonin treatment. We also found that cardamonin suppressed IL-1ß-activated nuclear factor (NF)-κB pathway, and the phosphorylation of signal transducer and activator of transcription (STAT)3. Furthermore, cardamonin treatment enhanced the expression of the antioxidant enzymes, heme oxygenase (HO)-1 and NAD(P)H dehydrogenase [quinone] 1 (NQO1), in HPDLCs. CONCLUSION: In this study, we found that cardamonin could suppress the production of inflammatory mediators in HPDLCs as well as the activation of several signaling pathways induced by IL-1ß treatment.

Chalcone-derivative L6H21 attenuates the OVA-induced asthma by targeting MD2.

Asthma represents a significant global challenge that affects individuals across all age groups and imposes substantial social and economic burden. Due to heterogeneity of the disease, not all patients obtain benefit with current treatments. The objective of this study was to explore the impact of MD2 on the progression of asthma using L6H21, a novel MD2 inhibitor, to identify potential targets and drug candidates for asthma treatment. To establish an asthma-related murine model and evaluate the effects of L6H21, ovalbumin (OVA) was used to sensitize and challenge mice. Pathological changes were examined with various staining techniques, such as H&E staining, glycogen staining, and Masson staining. Inflammatory cell infiltration and excessive cytokine secretion were evaluated by analyzing BALF cell count, RT-PCR, and ELISA. The TLR4/MD2 complex formation, as well as the activation of the MAPK and NF-кB pathways, was examined using western blot and co-IP. Treatment with L6H21 demonstrated alleviation of increased airway resistance, lung tissue injury, inflammatory cell infiltration and excessive cytokine secretion triggered by OVA. In addition, it also ameliorated mucus production and collagen deposition. In the L6H21 treatment group, inhibition of MAPK and NF-кB activation was observed, along with the disruption of TLR4/MD2 complex formation, in contrast to the model group. Thus, L6H21 effectively reduced the formation of the MD2 and TLR4 complex induced by OVA in a dose-dependent manner. This reduction resulted in the attenuation of MAPKs/NF-κB activation, enhanced suppression of inflammatory factor secretion, reduced excessive recruitment of inflammatory cells, and ultimately mitigated airway damage. MD2 emerges as a crucial target for asthma treatment, and L6H21, as an MD2 inhibitor, shows promise as a potential drug candidate for the treatment of asthma.

Synthesis, anticancer activity, molecular docking and molecular dynamics studies of some pyrazole-chalcone hybrids.

Four new hybrid compounds (H1-H4) bearing pyrazole (S1 and S2) and chalcone (P1 and P2) fragments were synthesized and characterized. Compounds were assayed for their ability to inhibit the proliferation of human lung (A549) and colon (Caco-2) cancer cell lines. Besides, toxicity against normal cells was determined using the human umbilical vein endothelial cells (HUVEC). In silico molecular docking, molecular dynamics (MD) simulation and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were carried out to predict the binding modes, protein stability, drug-likeness and toxicity of the reported compounds. The in vitro anticancer activity of the tested compounds revealed dose-dependent cell-specific cytotoxicity. In silico studies revealed that the compounds have a good binding affinity, possess appropriate drug-likeness properties and have low toxicity profiles.Communicated by Ramaswamy H. Sarma.

4-Nitrochalcone as a potential drug in non-clinical breast cancer studies.

Breast cancer is a high-magnitude public health problem, continually challenging physicians and scientists worldwide in the field of drug therapy. 4-nitrochalcone (4NC) is a phenolic compound that has promising antitumor activity in vitro, but its application in breast cancer treatment is still poorly explored. This study aimed to evaluate the action of 4NC in vitro and in vivo breast cancer models. The cytotoxic potential of 4NC was tested towards MCF-7 and MDA-MD-231 breast cancer cells, with a lower impact in the non-tumor lineage HB4a. For in vivo studies, solid Ehrlich carcinoma (SEC) was used, a syngeneic mouse model with non-nuclear estrogen and progesterone positivity, characterized by immunohistochemistry. Daily oral administration of 4NC (25 mg kg-1) for 21 days led to a consistent reduction in tumor growth compared to the vehicle group. No signs of toxicity evaluated by hematological, biochemical, histological, and oxidative stress parameters were observed in mice, and the DL50 was >2000 mg kg-1. The effectors Raptor and S6K1 showed decreased activation, with a consequent reduction in protein synthesis; concomitantly, there was an increase in LC3-II levels, but the protective autophagic response was not completed, with the maintenance of p62 levels and cell death. These results open new possibilities for the use of 4NC as a tumor cell metabolism modulating agent.

Design, synthesis and bioevaluation of novel prenylated chalcones derivatives as potential antitumor agents.

A series of novel prenylated chalcone derivatives with broad spectrum anticancer potential were designed and synthesized. Some of the synthesized target compounds showed potent anti-proliferative activities toward LNCaP (prostate cancer cell line), K562 (human leukemia cells), A549 (human lung carcinoma cell line) and HeLa (cervical cancer cell line) cell lines. Among of the active compounds, (E)-1-(4-(2-(diethylamino)ethoxy)-2-hydroxy-6-methoxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (C36) was directly interacted with protein kinase B (PKB), also known as AKT, significantly inhibited the pPI3K, pAKT(Ser473) protein levels to repress the growth of cancer cells by inducing apoptosis, arresting cell cycle. Our studies provide support for prenylated chalcone derivatives potential applications in cancer treatment as a potential AKT inhibitor.