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iTRAQ-based proteomic identification of proteins involved in anti-angiogenic effects of Panduratin A on HUVECs

Lai SL, Wong PF, Lim TK, Lin Q, Mustafa MR

Phytomedicine, 2015 Jan 15;22(1):203-12.
PMID: 25636890 DOI: 10.1016/j.phymed.2014.11.016

Panduratin A (PA), a cyclohexanyl chalcone from Boesenbergia rotunda (L.) Mansf. was shown to possess anti-angiogenic effects in our previous study. In the present study, the molecular targets and anti-angiogenic mechanisms of PA on human umbilical vein endothelial cells (HUVECs) were identified using an iTRAQ-based quantitative proteomics approach. A total of 263 proteins were found to be differentially regulated in response to treatment with PA. Ingenuity Pathway Analysis revealed that cellular growth and proliferation, protein synthesis, RNA post-transcriptional modification, cellular assembly and organization and cell-to-cell signaling and interaction were the most significantly deregulated molecular and cellular functions in PA-treated HUVECs. PA inhibited the expressions of ARPC2 and CTNND1 that are associated with the formation of actin cytoskeleton, focal adhesion and cellular protrusions. In addition, PA down-regulated CD63, GRB-2, ICAM-2 and STAB-1 that are implicated in adhesion, migration and tube formation of endothelial cells. The differential expressions of three targets, namely, ARPC2, CDK4, and GRB-2 were validated by western blot analyses. Furthermore, PA inhibited G1-S progression, and resulted in G0/G1 arrest in HUVECs. The blockage in cell cycle progression was accompanied with the suppression of mTOR signaling. Treatment of HUVECs with PA resulted in decreased phosphorylation of ribosomal S6 and 4EBP1 proteins, the two downstream effectors of mTOR signaling. We further showed that PA is able to inhibit mTOR signaling induced by VEGF, a potent inducer of angiogenesis. Taken together, by integrating quantitative proteomic approach, we identified protein targets in which PA mediates its anti-angiogenic effects. The present study thus provides mechanistic evidence to the previously reported multifaceted anti-angiogenic effects of PA. Our study further identified mTOR signaling as an important target of PA, and therefore highlights the potential of PA for therapeutic intervention against angiogenesis-related pathogenesis, particularly, metastatic malignancy.

Matched MeSH terms: Chalcones/pharmacology*
Fulltext Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling

Hariono M, Choi SB, Roslim RF, Nawi MS, Tan ML, Kamarulzaman EE, et al.

PLoS One, 2019;14(1):e0210869.
PMID: 30677071 DOI: 10.1371/journal.pone.0210869

Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174.

Matched MeSH terms: Chalcones/pharmacology
The role of chalcones: helichrysetin, xanthohumol, and flavokawin-C in promoting neurite outgrowth in PC12 Adh cells

Phan CW, Sabaratnam V, Yong WK, Abd Malek SN

Nat Prod Res, 2018 May;32(10):1229-1233.
PMID: 28539058 DOI: 10.1080/14786419.2017.1331226

Chalcones are a group of compounds widely distributed in plant kingdom. The aim of this study was to assess the neurite outgrowth stimulatory activity of selected chalcones, namely helichrysetin, xanthohumol and flavokawin-C. Using adherent rat pheochromocytoma (PC12 Adh) cells, the chalcones were subjected to neurite outgrowth assay and the extracellular nerve growth factor (NGF) levels were determined. Xanthohumol (10 μg/mL) displayed the highest (p

Matched MeSH terms: Chalcones/pharmacology*
Synthesis, molecular docking and anti-diabetic studies of novel benzimidazole-pyrazoline hybrid molecules

Ibraheem F, Ahmad M, Ashfaq UA, Aslam S, Khan ZA, Sultan S

Pak J Pharm Sci, 2020 Mar;33(2(Supplementary)):847-854.
PMID: 32863261

Pyrazoline and benzimidazoles derivatives have been widely studied due to their potential applications in the medicinal field. In this research project, we have hybridized these two heterocyclic systems in the same molecule. A new series of compounds, 2-((3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-1H-benzo[d]imidazole (5a-i) were synthesized through a multistep reaction. In the first step, chalcones 3a-i were prepared by coupling of various acetophenones and benzaldehydes under alkaline conditions. These chalcones were cyclized with hydrazine hydrate to form a series of pyrazolines which were finally coupled with 2-chloromethyl-1H-benzimidazole to get a new series of titled hybrid molecules. The structures of these compounds were elucidated by spectral (1H NMR and 13C NMR) analysis. The anti-diabetic potential of these compounds was studied by screening them for their α-glucosidase inhibition activity. The SAR was established through molecular docking analysis. Compound 5d appeared as effective inhibitor with IC50 = 50.06μM as compared to reference drug (acarbose) having IC50 = 58.8μM.

Matched MeSH terms: Chalcones/pharmacology
Fulltext Synthesis, Structure, Carbohydrate Enzyme Inhibition, Antioxidant Activity, In Silico Drug-Receptor Interactions and Drug-Like Profiling of the 5-Styryl-2-Aminochalcone Hybrids

Mphahlele MJ, Agbo EN, Choong YS

Molecules, 2021 May 04;26(9).
PMID: 34064448 DOI: 10.3390/molecules26092692

The 2-amino-5-(3/4-fluorostyryl)acetophenones were prepared and reacted with benzaldehyde derivatives to afford the corresponding 5-styryl-2-aminochalcone hybrids. The trans geometry of the styryl and α,β-unsaturated carbonyl arms, and the presence of NH…O intramolecular hydrogen bond were validated using 1H-NMR and X-ray data. The 2-amino-5-styrylacetophenones and their 5-styryl-2-aminochalcone derivatives were screened in vitro for their capability to inhibit α-glucosidase and/or α-amylase activities. Their antioxidant properties were evaluated in vitro through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) free radical scavenging assays. Kinetic studies of the most active derivatives from each series against α-glucosidase and/or α-amylase activities have been performed supported by molecular docking studies to determine plausible protein-ligand interactions on a molecular level. The key aspects of the pharmacokinetics of these compounds, i.e., absorption, distribution, metabolism, and excretion have also been simulated at theoretical level. The most active compounds from each series, namely, 2a and 3e, were evaluated for cytotoxicity against the normal monkey kidney cells (Vero cells) and the adenocarcinomic human epithelial (A549) cell line to establish their safety profile at least in vitro.

Matched MeSH terms: Chalcones/pharmacology*
Synthesis, Molecular Docking and Biological Activity Evaluation of Alkoxy Substituted Chalcone Derivatives: Potential Apoptosis Inducing Agent on MCF-7 Cells

Khairul WM, Hashim F, Mohammed M, Shah NSMN, Johari SATT, Rahamathullah R, et al.

Anticancer Agents Med Chem, 2021;21(13):1738-1750.
PMID: 33176667 DOI: 10.2174/1871520620999201110190709

INTRODUCTION: In this contribution, a series of alkoxy substituted chalcones were successfully designed, synthesized, spectroscopically characterized and evaluated for their cytotoxicity potential in inhibiting the growth of MCF-7 cells.
OBJECTIVE: In order to investigate the influence between electron density in conjugated π-systems and biological activities, different withdrawing substituents, namely Nitro (NO2), Cyano (C≡N) and trifluoromethyl (CF3) were introduced in the chalcone-based molecular system.
METHODS: All the derivatives were then tested on MCF-7 cell line using the fluorescence microscopy-based cytotoxicity analyses.
RESULTS: The preliminary findings showed that both -NO2 and -CF3 substituents revealed their potential to inhibit the growth of MCF-7 with IC;50 values of 14.75 and 13.75 μg/ml, respectively. In addition, the morphological changes of MCF-7 cells were observed in response to alkoxy substituted chalcone treatment through an induction of apoptosis pathway with cell blebbing, phosphatidylserine exposure and autophagic activity with acidification of lysosomal structure. Intermolecular interaction based on in silico investigation on nitro, trifluoromethyl and cyano based chalcones exhibited several types of interactions with tumor necrosis factor receptor (PDB: 1EXT) protein and high hydrogen bond in the molecule-receptor interaction have given significant impact towards their toxicity on MCF-7 cells.
CONCLUSION: Significantly, these types of chalcones exhibited ideal and high potential to be further developed as anti-cancer agents.

Matched MeSH terms: Chalcones/pharmacology*
Fulltext Synthesis, Biological Evaluation and Molecular Modelling of 2'-Hydroxychalcones as Acetylcholinesterase Inhibitors

Sukumaran SD, Chee CF, Viswanathan G, Buckle MJ, Othman R, Abd Rahman N, et al.

Molecules, 2016 Jul 22;21(7).
PMID: 27455222 DOI: 10.3390/molecules21070955

A series of 2'-hydroxy- and 2'-hydroxy-4',6'-dimethoxychalcones was synthesised and evaluated as inhibitors of human acetylcholinesterase (AChE). The majority of the compounds were found to show some activity, with the most active compounds having IC50 values of 40-85 µM. Higher activities were generally observed for compounds with methoxy substituents in the A ring and halogen substituents in the B ring. Kinetic studies on the most active compounds showed that they act as mixed-type inhibitors, in agreement with the results of molecular modelling studies, which suggested that they interact with residues in the peripheral anionic site and the gorge region of AChE.

Matched MeSH terms: Chalcones/pharmacology*
Fulltext Synthesis of chalcones with anticancer activities

Syam S, Abdelwahab SI, Al-Mamary MA, Mohan S

Molecules, 2012 May 25;17(6):6179-95.
PMID: 22634834 DOI: 10.3390/molecules17066179

Several chalcones were synthesized and their in vitro cytotoxicity against various human cell lines, including human breast adenocarcinoma cell line MCF-7, human lung adenocarcinoma cell line A549, human prostate cancer cell line PC3, human adenocarcinoma cell line HT-29 (colorectal cancer) and human normal liver cell line WRL-68 was evaluated. Most of the compounds being active cytotoxic agents, four of them with minimal IC₅₀ values were chosen and studied in detail with MCF-7 cells. The compounds 1, 5, 23, and 25 were capable in eliciting apoptosis in MCF-7 cells as shown by multiparameter cytotoxicity assay and caspase-3/7, -8, and -9 activities (p < 0.05). The ROS level showed 1.3-fold increase (p < 0.05) at the low concentrations used and thus it was concluded that the compounds increased the ROS level eventually leading to apoptosis in MCF-7 cells through intrinsic as well as extrinsic pathways.

Matched MeSH terms: Chalcones/pharmacology*
Synthesis of azachalcones, their α-amylase, α-glucosidase inhibitory activities, kinetics, and molecular docking studies

Saleem F, Kanwal, Khan KM, Chigurupati S, Solangi M, Nemala AR, et al.

Bioorg Chem, 2021 01;106:104489.
PMID: 33272713 DOI: 10.1016/j.bioorg.2020.104489

Diabetes being a chronic metabolic disorder have attracted the attention of medicinal chemists and biologists. The introduction of new and potential drug candidates for the cure and treatment of diabetes has become a major concern due to its increased prevelance worldwide. In the current study, twenty-seven azachalcone derivatives 3-29 were synthesized and evaluated for their antihyperglycemic activities by inhibiting α-amylase and α-glucosidase enzymes. Five compounds 3 (IC50 = 23.08 ± 0.03 µM), (IC50 = 26.08 ± 0.43 µM), 5 (IC50 = 24.57 ± 0.07 µM), (IC50 = 27.57 ± 0.07 µM), 6 (IC50 = 24.94 ± 0.12 µM), (IC50 = 27.13 ± 0.08 µM), 16 (IC50 = 27.57 ± 0.07 µM), (IC50 = 29.13 ± 0.18 µM), and 28 (IC50 = 26.94 ± 0.12 µM) (IC50 = 27.99 ± 0.09 µM) demonstrated good inhibitory activities against α-amylase and α-glucosidase enzymes, respectively. Acarbose was used as the standard in this study. Structure-activity relationship was established by considering the parent skeleton and different substitutions on aryl ring. The compounds were also subjected for kinetic studies to study their mechanism of action and they showed competitive mode of inhibition against both enzymes. The molecular docking studies have supported the results and showed that these compounds have been involved in various binding interactions within the active site of enzyme.

Matched MeSH terms: Chalcones/pharmacology*
Proteomic analysis of flavokawain C-induced cell death in HCT 116 colon carcinoma cell line

Phang CW, Gandah NA, Abd Malek SN, Karsani SA

Eur J Pharmacol, 2019 Jun 15;853:388-399.
PMID: 31014923 DOI: 10.1016/j.ejphar.2019.04.032

Flavokawain C (FKC), a naturally occurring chalcone, has previously been shown to inhibit the growth of colon carcinoma HCT 116 cells through induction of apoptosis and cell cycle arrest. However, the possible underlying mechanisms of cell death as a response to FKC treatment remains unclear. In this study, we performed proteomic analysis of HCT 116 cells treated with FKC to identify proteins that change in abundance. This was followed by bioinformatic analysis to predict possible associated molecular targets or pathways involved in the observed effects of FKC. A total of 35 proteins that changed in abundance (17 increased and 18 decreased) were identified through two-dimensional gel electrophoresis followed by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Using the Ingenuity Pathway Analysis (IPA), these proteins were predicted to be involved in cell death and survival, cell cycle, cellular growth and proliferation, protein synthesis, post-translational modification and amino acid metabolism by. Further analysis of the transcript levels of selected proteins using qPCR showed that some of the genes exhibited similar change of profile to that of the proteins'. Our results have provided novel insights into the potential molecular mechanisms underlying FKC-induced apoptosis or cell death in colon cancer cells.

Matched MeSH terms: Chalcones/pharmacology*
Fulltext Preliminary Insight of Pyrrolylated-Chalcones as New Anti-Methicillin-Resistant Staphylococcus aureus (Anti-MRSA) Agents

Gunasekharan M, Choi TI, Rukayadi Y, Mohammad Latif MA, Karunakaran T, Mohd Faudzi SM, et al.

Molecules, 2021 Sep 01;26(17).
PMID: 34500755 DOI: 10.3390/molecules26175314

Bacterial infections are regarded as one of the leading causes of fatal morbidity and death in patients infected with diseases. The ability of microorganisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), to develop resistance to current drugs has evoked the need for a continuous search for new drugs with better efficacies. Hence, a series of non-PAINS associated pyrrolylated-chalcones (1-15) were synthesized and evaluated for their potency against MRSA. The hydroxyl-containing compounds (8, 9, and 10) showed the most significant anti-MRSA efficiency, with the MIC and MBC values ranging from 0.08 to 0.70 mg/mL and 0.16 to 1.88 mg/mL, respectively. The time-kill curve and SEM analyses exhibited bacterial cell death within four hours after exposure to 9, suggesting its bactericidal properties. Furthermore, the docking simulation between 9 and penicillin-binding protein 2a (PBP2a, PDB ID: 6Q9N) suggests a relatively similar bonding interaction to the standard drug with a binding affinity score of -7.0 kcal/mol. Moreover, the zebrafish model showed no toxic effects in the normal embryonic development, blood vessel formation, and apoptosis when exposed to up to 40 µM of compound 9. The overall results suggest that the pyrrolylated-chalcones may be considered as a potential inhibitor in the design of new anti-MRSA agents.

Matched MeSH terms: Chalcones/pharmacology*
Fulltext Panduratin A inhibits the growth of A549 cells through induction of apoptosis and inhibition of NF-kappaB translocation

Cheah SC, Appleton DR, Lee ST, Lam ML, Hadi AH, Mustafa MR

Molecules, 2011 Mar 21;16(3):2583-98.
PMID: 21441862 DOI: 10.3390/molecules16032583

In the present study we investigated the effects of panduratin A, isolated from Boesenbergia rotunda, on proliferation and apoptosis in A549 human non-small cell lung cancer cells. Cell proliferation and induction of apoptosis was determined by the real-time cellular analyzer (RTCA), MTT assay and High Content Screening (HCS). The RTCA assay indicated that panduratin A exhibited cytotoxicity, with an IC₅₀ value of 4.4 µg/mL (10.8 µM). Panduratin A arrested cancer cells labeled with bromodeoxyuridine (BrdU) and phospho-Histone H3 in the mitotic phase. The cytotoxic effects of panduratin A were found to be accompanied by a dose-dependent induction of apoptosis, as assessed by DNA condensation, nuclear morphology and intensity, cell permeability, mitochondrial mass/ potential, F-actin and cytochrome c. In addition, treatment with an apoptosis-inducing concentration of panduratin A resulted in significant inhibition of Nuclear Factor-kappa Beta (NF-κB) translocation from cytoplasm to nuclei activated by tumor necrosis factor-alpha (TNF-α), as illustrated by the HCS assay. Our study provides evidence for cell growth inhibition and induction of apoptosis by panduratin A in the A549 cell line, suggesting its therapeutic potential as an NF-κB inhibitor.

Matched MeSH terms: Chalcones/pharmacology*
Panduratin A induces protective autophagy in melanoma via the AMPK and mTOR pathway

Lai SL, Mustafa MR, Wong PF

Phytomedicine, 2018 Mar 15;42:144-151.
PMID: 29655680 DOI: 10.1016/j.phymed.2018.03.027

BACKGROUND: Targeting autophagy is emerging as a promising strategy in cancer therapeutics in recent years. Autophagy can be modulated to drive cancer cell deaths that are notoriously resistant to apoptotic-inducing drugs. In addition, autophagy has been implicated as a prosurvival mechanism in mediating cancer chemoresistance. Our previous study has demonstrated that Panduratin A (PA), a plant-derived active compound exploits ER-stress-mediated apoptosis as its cytotoxic mechanism on melanoma.
PURPOSE: Our previous proteomics analysis revealed that treatment with PA resulted in the upregulation of an autophagy marker, LC3B in melanoma cells. Therefore, the present study sought to investigate the role of PA-induced autophagy in melanoma cells.
METHODS: Transmission electron microscopy was performed for examination of autophagic ultra-structures in PA-treated A375 cells. Cytoplasmic LC3B and p62/SQSMT1 punctate structures were detected using immunofluorescene staining. Expression levels of LC3B II, p62/SQSMT1, ATG 12, Beclin 1, phospho S6 (ser235/236), phospho AMPK (Thr172) and cleaved PARP were evaluated by western blotting.
RESULTS: Autophagosomes, autolysosomes and punctuates of LC3 proteins could be observed in PA-treated A375 cells. PA-induced autophagy in A375 melanoma cells was found to be mediated through the inhibition of mTOR signaling and activation of AMPK pathway. Furthermore, we showed that PA-induced apoptosis was increased in the presence of an autophagy inhibitor, signifying the cytoprotective effect of PA-induced autophagy in melanoma cells.
CONCLUSION: Taken together, results from the present study suggest that the inhibition of autophagy by targeting mTOR and AMPK could potentiate the cytotoxicity effects of PA on melanoma cells.

Matched MeSH terms: Chalcones/pharmacology*
Fulltext Novel Semi-Synthetic Cu (II)-Cardamonin Complex Exerts Potent Anticancer Activity against Triple-Negative Breast and Pancreatic Cancer Cells via Inhibition of the Akt Signaling Pathway

Hossan MS, Break MKB, Bradshaw TD, Collins HM, Wiart C, Khoo TJ, et al.

Molecules, 2021 Apr 09;26(8).
PMID: 33918814 DOI: 10.3390/molecules26082166

Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)-cardamonin complex (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that 19 abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, 19 decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of 19 as a therapeutic agent for TNBC and pancreatic cancer.

Matched MeSH terms: Chalcones/pharmacology*
Natural-derived compounds and their mechanisms in potential autosomal dominant polycystic kidney disease (ADPKD) treatment

Mahendran R, Lim SK, Ong KC, Chua KH, Chai HC

Clin Exp Nephrol, 2021 Nov;25(11):1163-1172.
PMID: 34254206 DOI: 10.1007/s10157-021-02111-x

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic kidney disorder that impairs renal functions progressively leading to kidney failure. The disease affects between 1:400 and 1:1000 ratio of the people worldwide. It is caused by the mutated PKD1 and PKD2 genes which encode for the defective polycystins. Polycystins mimic the receptor protein or protein channel and mediate aberrant cell signaling that causes cystic development in the renal parenchyma. The cystic development is driven by the increased cyclic AMP stimulating fluid secretion and infinite cell growth. In recent years, natural product-derived small molecules or drugs targeting specific signaling pathways have caught attention in the drug discovery discipline. The advantages of natural products over synthetic drugs enthusiast researchers to utilize the medicinal benefits in various diseases including ADPKD.
CONCLUSION: Overall, this review discusses some of the previously studied and reported natural products and their mechanisms of action which may potentially be redirected into ADPKD.

Matched MeSH terms: Chalcones/pharmacology*
Inhibitory effect of compounds from Zingiberaceae species on human platelet aggregation

Jantan I, Raweh SM, Sirat HM, Jamil S, Mohd Yasin YH, Jalil J, et al.

Phytomedicine, 2008 Apr;15(4):306-9.
PMID: 17913483

Twelve compounds isolated from Alpinia mutica Roxb., Kaempferia rotunda Linn., Curcuma xanthorhiza Roxb., Curcuma aromatica Valeton and Zingiber zerumbet Smith (Family: Zingiberaceae) and three synthesized derivatives of xanthorrhizol were evaluated for their ability to inhibit arachidonic acid- (AA), collagen- and ADP-induced platelet aggregation in human whole blood. Antiplatelet activity of the compounds was measured in vitro by the Chrono Log whole blood aggregometer using an electrical impedance method. Among the compounds tested, curcumin from C. aromatica, cardamonin, pinocembrine and 5,6-dehydrokawain from A. mutica and 3-deacetylcrotepoxide from K. rotunda showed strong inhibition on platelet aggregation induced by AA with IC(50) values of less than 84 microM. Curcumin was the most effective antiplatelet compound as it inhibited AA-, collagen- and ADP-induced platelet aggregation with IC(50) values of 37.5, 60.9 and 45.7 microM, respectively.

Matched MeSH terms: Chalcones/pharmacology
Inhibition of prostaglandin E(2) production by synthetic minor prenylated chalcones and flavonoids: synthesis, biological activity, crystal structure, and in silico evaluation

Rullah K, Mohd Aluwi MF, Yamin BM, Abdul Bahari MN, Wei LS, Ahmad S, et al.

Bioorg Med Chem Lett, 2014 Aug 15;24(16):3826-34.
PMID: 25027933 DOI: 10.1016/j.bmcl.2014.06.061

The discovery of potent inhibitors of prostaglandin E2 (PGE2) synthesis in recent years has been proven to be an important game changer in pharmaceutical industry. It is known that excessive production of PGE2 triggers a vast array of biological signals and physiological events that contributes to inflammatory diseases such as rheumatoid arthritis, atherosclerosis, cancer, and pain. In this Letter, we report the synthesis of a series of minor prenylated chalcones and flavonoids which was found to be significantly active in suppressing the PGE2 production secreted by lipopolysaccharide-induced mouse macrophage cells (RAW 264.7). Among the compounds tested, 14b showed a dose-response inhibition of PGE2 production with an IC50 value of 2.1 μM. The suppression upon PGE2 secretion was not due to cell death since 14b did not reduce the cell viability in close proximity to the PGE2 inhibition concentration. The obtained atomic coordinates for the single-crystal XRD of 14b was then applied in the docking simulation to determine the potential important binding interactions with murine COX-2 and mPGES-1 putative binding sites.

Matched MeSH terms: Chalcones/pharmacology*
Inhibition of nitric oxide and prostaglandin E2 production by pyrrolylated-chalcones: Synthesis, biological activity, crystal structure analysis, and molecular docking studies

Mohd Faudzi SM, Abdullah MA, Abdull Manap MR, Ismail AZ, Rullah K, Mohd Aluwi MFF, et al.

Bioorg Chem, 2020 01;94:103376.
PMID: 31677861 DOI: 10.1016/j.bioorg.2019.103376

In search of potent anti-inflammatory agents, twenty-four chalcone derivatives including seven new compounds (13 - 17, 21 and 23) containing pyrrole moiety were designed, synthesized, and assessed for their nitric oxide (NO) and prostaglandin E2 (PGE2) suppression ability on IFN-γ/LPS-induced RAW 264.7 macrophage cells. Results showed that none of the synthesized compounds were PAINS-associated molecules, with 3-(2,5-dimethoxyphenyl)-1-(1H-pyrrol-2-yl)-prop-2-en-1-one (compound 16) exhibiting remarkable inhibition activity towards PGE2 and NO production with IC50 values of 0.5 ± 1.5 µM and 12.1 ± 1.5 µM, respectively. Physicochemical and ADMET studies showed that majority of the compounds obey to Lipinski's rule of five (RO5) having high blood brain barrier (BBB) penetration, human intestinal absorption (HIA), P- glycoprotein (PgP) inhibition and plasma binding protein (PPB) inhibition. The obtained atomic coordinates for the single-crystal XRD of 16 were then applied in a molecular docking simulation, and compound 16 was found to participate in a number of important binding interactions in the binding sites of ERK and mPGES-1. Based on these results, we have observed the potential of compound 16 as a new hit anti-inflammatory agent, and these findings could serve as a basis for further studies on its mechanism of action.

Matched MeSH terms: Chalcones/pharmacology*
Fulltext Inhibition of Epithelial CC-Family Chemokine Synthesis by the Synthetic Chalcone DMPF-1 via Disruption of NF-κB Nuclear Translocation and Suppression of Experimental Asthma in Mice

Rajajendram R, Tham CL, Akhtar MN, Sulaiman MR, Israf DA

Mediators Inflamm, 2015;2015:176926.
PMID: 26300589 DOI: 10.1155/2015/176926

Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The interaction between airway epithelium and inflammatory mediators plays a key role in the pathogenesis of asthma. In vitro studies evaluated the inhibitory effects of 3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DMPF-1), a synthetic chalcone analogue, upon inflammation in the A549 lung epithelial cell line. DMPF-1 selectively inhibited TNF-α-stimulated CC chemokine secretion (RANTES, eotaxin-1, and MCP-1) without any effect upon CXC chemokine (GRO-α and IL-8) secretion. Western blot analysis further demonstrated that the inhibitory activity resulted from disruption of p65NF-κB nuclear translocation without any effects on the mitogen-activated protein kinase (MAPK) pathway. Treatment of ovalbumin-sensitized and ovalbumin-challenged BALB/c mice with DMPF-1 (0.2-100 mg/kg) demonstrated significant reduction in the secretion and gene expression of CC chemokines (RANTES, eotaxin-1, and MCP-1) and Th2 cytokines (IL-4, IL-5, and IL-13). Furthermore, DMPF-1 treatment inhibited eosinophilia, goblet cell hyperplasia, peripheral blood total IgE, and airway hyperresponsiveness in ovalbumin-sensitized and ovalbumin-challenged mice. In conclusion, these findings demonstrate the potential of DMPF-1, a nonsteroidal compound, as an antiasthmatic agent for further pharmacological evaluation.

Matched MeSH terms: Chalcones/pharmacology*
Fulltext Induction of selective cytotoxicity and apoptosis in human T4-lymphoblastoid cell line (CEMss) by boesenbergin a isolated from boesenbergia rotunda rhizomes involves mitochondrial pathway, activation of caspase 3 and G2/M phase cell cycle arrest

Ng KB, Bustamam A, Sukari MA, Abdelwahab SI, Mohan S, Buckle MJ, et al.

BMC Complement Altern Med, 2013;13:41.
PMID: 23432947 DOI: 10.1186/1472-6882-13-41

Boesenbergia rotunda (Roxb.) Schlecht (family zingiberaceae) is a rhizomatous herb that is distributed from north-eastern India to south-east Asia, especially in Indonesia, Thailand and Malaysia. Previous research has shown that the crude extract of this plant has cytotoxic properties. The current study examines the cytotoxic properties of boesenbergin A isolated from Boesenbergia rotunda.

Matched MeSH terms: Chalcones/pharmacology

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