MyMedR

Erythrocarpines A-E, new cytotoxic limonoids from Chisocheton erythrocarpus

Awang K, Lim CS, Mohamad K, Morita H, Hirasawa Y, Takeya K, et al.

Bioorg Med Chem, 2007 Sep 1;15(17):5997-6002.

Five new cytotoxic limonoids, erythrocarpines A-E (1-5), were isolated from the bark of Chisocheton erythrocarpus Hiern. Chemical structures, stereochemistry, and conformation were fully elucidated and characterized by 2D NMR, MS, and computational methods.

Fulltext 2,7-Dihydr-oxy-3,6-dimethoxy-phenanthrene from Dehaasia longipedicellata

Mukhtar MR, Nafiah MA, Awang K, A Hadi AH, Ng SW

Acta Crystallogr Sect E Struct Rep Online, 2008;64(Pt 6):o1135.

PMID: 21202644 DOI: 10.1107/S1600536808014451

The hydr-oxy groups in the title compound, C(16)H(14)O(4), are each hydrogen bonded to the adjacent meth-oxy O atom; one of the two hydr-oxy groups is additionally linked to the O atom of the meth-oxy group of another mol-ecule, forming a linear chain.

New alkaloids from Phoebe grandis (Nees) Merr

Awang K, Mukhtar MR, Hadi AH, Litaudon M, Latip J, Abdullah NR

Nat Prod Res, 2006 May 20;20(6):567-72.

PMID: 16835089

The alkaloidal extract of the leaves of Phoebe grandis (nees) merr. have provided two new minor alkaloids; phoebegrandine D (1), a proaporphine-tryptamine dimer, and phoebegrandine E (2), an indoloquinolizidine. This is the first report on the occurrence of an indoloquinolizidine in the Phoebe species. The crude extract also exhibited antiplasmodial activity (IC50<8 microg mL-1). The structures of the novel compounds were elucidated by spectroscopic methods, notably 2D NMR and HRMS.

Antimicrobial compounds from Alpinia conchigera

Aziz AN, Ibrahim H, Rosmy Syamsir D, Mohtar M, Vejayan J, Awang K

J Ethnopharmacol, 2013 Feb 13;145(3):798-802.

PMID: 23266278 DOI: 10.1016/j.jep.2012.12.024

The rhizome of Alpinia conchigerahas been used as a condiment in the northern states of Peninsular Malaysia and occasionally in folk medicine in the east coast to treat fungal infections. In some states of Peninsular Malaysia, the rhizomes are consumed as a post-partum medicine and the young shoots are prepared into a vegetable dish. This study aimed to investigate the chemical constituents of the pseudostems and rhizomes of Malaysian Alpinia conchigera and to evaluate the antimicrobial activity of the dichloromethane (DCM) extracts of the pseudostems, rhizomes and the isolated compounds against three selected fungi and five strains of Staphylococcus aureus.

Lepidotol A from Mesua lepidota Inhibits Inflammatory and Immune Mediators in Human Endothelial Cells

Rouger C, Derbré S, Charreau B, Pabois A, Cauchy T, Litaudon M, et al.

J Nat Prod, 2015 Sep 25;78(9):2187-97.

PMID: 26301802 DOI: 10.1021/acs.jnatprod.5b00222

Phytochemical investigation on the fruits of Mesua lepidota (Calophyllaceae) led to the isolation of seven new phenylcoumarin derivatives named lepidotols A-E (1-5) and lepidotins A and B (6, 7). These structures were elucidated by spectroscopic and spectrometric methods including UV, NMR, and HRMS. Lepidotol A (1), the major compound, was evaluated for its inhibitory effect on inflammation and immunity using endothelial cell-based cellular assays. At 10 μM, 1 exhibited an anti-inflammatory activity, with a significant inhibition of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 expression induced by tumor necrosis factor-α. Lepidotol A also showed a mild immunosuppressive effect, with inhibition of the major histocompatibility complex molecules, namely, human leukocyte antigen (HLA)-DR and HLA-E.

Curcumenol isolated from Curcuma zedoaria suppresses Akt-mediated NF-κB activation and p38 MAPK signaling pathway in LPS-stimulated BV-2 microglial cells

Lo JY, Kamarudin MN, Hamdi OA, Awang K, Kadir HA

Food Funct, 2015 Nov;6(11):3550-9.

PMID: 26301513 DOI: 10.1039/c5fo00607d

Curcumenol, a sesquiterpene isolated from Curcuma zedoaria is known to possess a variety of health and medicinal values which includes neuroprotection, anti-inflammatory, anti-tumor and hepatoprotective activities. The current study aim is to investigate the modulatory effects of curcumenol towards the lipopolysaccharides (LPS)-induced inflammation in BV-2 microglia. Curcumenol markedly decreased LPS-induced production of nitric oxide (NO), pro-inflammatory cytokines [(IL-6) and (TNF-α)] and pro-inflammatory proteins expression, iNOS and COX-2. Moreover, curcumenol inhibited NF-κB activation by suppressing the nuclear translocation of the NF-κB p65 subunit and blocking IκBα phosphorylation and degradation. Furthermore, an NF-κB inhibitor, ethyl 3,4-dihydroxycinnamate also known as caffeic acid ethyl ester (CAEE), attenuated LPS-stimulated iNOS and COX-2 expression, suggesting that NF-κB inhibition is a regulator in the expression of iNOS and COX-2 proteins. Further mechanistic study with an Akt inhibitor, triciribine hydrate (API-2), revealed that curcumenol acted through Akt-dependent NF-κB activation. Moreover, curcumenol inhibition on LPS-induced phosphorylation of p38 MAPK is confirmed by its inhibitor (SB 202190). These results indicate that curcumenol diminishes the proinflammatory mediators and the expression of the regulatory genes in LPS-stimulated BV-2 by inhibiting Akt-dependent NF-κB activation and downregulation of Akt and p38 MAPKs signaling.

Acylphenols and dimeric acylphenols from Myristica maxima Warb

Othman MA, Sivasothy Y, Looi CY, Ablat A, Mohamad J, Litaudon M, et al.

Fitoterapia, 2016 Jun;111:12-7.

PMID: 27072985 DOI: 10.1016/j.fitote.2016.04.004

Giganteone E (1), a new dimeric acylphenol was isolated as a minor constituent from the bark of Myristica maxima Warb. The structure of 1 was established on the basis of 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Malabaricones A-C (2-4), giganteones A and C (5 and 6), maingayones A and B (7 and 8), maingayic acid B (9) and β-sitosteryl oleate (10) were also characterized in this plant for the first time. Compound 10 was identified for the first time in the Myristicaceae. Compounds 2 and 5 were active against human prostate cancer cell-lines, thus making this the first report on the prostate cancer inhibiting potential of acylphenols and dimeric acylphenols. Compounds 1, 4, 5, 7 and 8 exhibited potent DPPH free radical scavenging activity. This is the first report on their free radical scavenging capacity.

Fulltext Geranylated 4-Phenylcoumarins Exhibit Anticancer Effects against Human Prostate Cancer Cells through Caspase-Independent Mechanism

Suparji NS, Chan G, Sapili H, Arshad NM, In LL, Awang K, et al.

PLoS One, 2016;11(3):e0151472.

PMID: 26974436 DOI: 10.1371/journal.pone.0151472

Geranylated 4-phenylcoumarins, DMDP-1 & -2 isolated from Mesua elegans were investigated for anticancer potential against human prostate cancer cells. Treatment with DMDP-1 & -2 resulted in cell death in a time and dose dependent manner in an MTT assay on all cancer cell lines tested with the exception of lung adenocarcinoma cells. DMDP-1 showed highest cytotoxic efficacy in PC-3 cells while DMDP-2 was most potent in DU 145 cells. Flow cytometry indicated that both coumarins were successful to induce programmed cell death after 24 h treatment. Elucidation on the mode-of-action via protein arrays and western blotting demonstrated death induced without any significant expressions of caspases, Bcl-2 family proteins and cleaved PARP, thus suggesting the involvement of caspase-independent pathways. In identifying autophagy, analysis of GFP-LC3 showed increased punctate in PC-3 cells pre-treated with CQ and treated with DMDP-1. In these cells decreased expression of autophagosome protein, p62 and cathepsin B further confirmed autophagy. In contrary, the DU 145 cells pre-treated with CQ and treated with DMDP-2 has reduced GFP-LC3 punctate although the number of cells with obvious GFP-LC3 puncta was significantly increased in the inhibitor-treated cells. The increase level of p62 suggested leakage of cathepsin B into the cytosol to trigger potential downstream death mediators. This correlated with increased expression of cathepsin B and reduced expression after treatment with its inhibitor, CA074. Also auto-degradation of calpain-2 upon treatment with DMDP-1 &-2 and its inhibitor alone, calpeptin compared with the combination treatment, further confirmed involvement of calpain-2 in PC-3 and DU 145 cells. Treatment with DMDP-1 & -2 also showed up-regulation of total and phosphorylated p53 levels in a time dependent manner. Hence, DMDP-1 & -2 showed ability to activate multiple death pathways involving autophagy, lysosomal and endoplasmic reticulum death proteins which could potentially be manipulated to develop anti-cancer therapy in apoptosis resistant cells.

Fulltext In vitro antiplasmodial and antioxidant activities of bisbenzylisoquinoline alkaloids from Alseodaphne corneri Kosterm

Zahari A, Ablat A, Sivasothy Y, Mohamad J, Choudhary MI, Awang K

Asian Pac J Trop Med, 2016 Apr;9(4):328-332.

PMID: 27086149 DOI: 10.1016/j.apjtm.2016.03.008

OBJECTIVE: To study antiplasmodial and antioxidant activities of the isolation of alkaloids from the active dichloromethane extract of Alseodaphne corneri.

METHODS: Phytochemical studies of the crude extract led to the isolation of six alkaloids using recycle high performance liquid chromatography and preparative thin layer chromatography. The antiplasmodial activity of the isolated compounds was evaluated using the histidine-rich protein II assay. The isolated alkaloids were also tested for their antioxidant activity using three different assays; DPPH, ferric reducing ability of plasma and metal chelating assays.

RESULTS: Malaria infection caused the formation of free radicals which subsequently led to oxidative stress and apoptosis. The antioxidant properties of the alkaloids under investigation revealed that in addition to the antiplasmodial activity, the alkaloids could also prevent oxidative stress. (+)-laurotetanine and (+)-norstephasubine exhibited strong antiplasmodial activities with IC50 values of 0.189 and 0.116 μM, respectively.

CONCLUSIONS: Interestingly, the two most potent compounds that exhibit antiplasmodial activity also exhibit good antioxidant activities. The crude dichloromethane extract and the isolated compounds exert substantial antiplasmodial and antioxidative activities which in turn suppress oxidative stress and cause less damage to the host.

Anacardic Acids from Knema hookeriana as Modulators of Bcl-xL/Bak and Mcl-1/Bid Interactions

Gény C, Rivière G, Bignon J, Birlirakis N, Guittet E, Awang K, et al.

J Nat Prod, 2016 Apr 22;79(4):838-44.

PMID: 27008174 DOI: 10.1021/acs.jnatprod.5b00915

Proteins of the Bcl-2 family are key targets in anticancer drug discovery. Disrupting the interaction between anti- and pro-apoptotic members of this protein family was the approach chosen in this study to restore apoptosis. Thus, a biological screening on the modulation of the Bcl-xL/Bak and Mcl-1/Bid interactions permitted the selection of Knema hookeriana for further phytochemical investigations. The ethyl acetate extract from the stem bark led to the isolation of six new compounds, three acetophenone derivatives (1-3) and three anacardic acid derivatives (4-6), along with four known anacardic acids (7-10) and two cardanols (11, 12). Their structures were elucidated by 1D and 2D NMR analysis in combination with HRMS experiments. The ability of these compounds to antagonize Bcl-xL/Bak and Mcl-1/Bid association was determined, using a protein-protein interaction assay, but only anacardic acid derivatives (4-10) exhibited significant binding properties, with Ki values ranging from 0.2 to 18 μM. Protein-ligand NMR experiments further revealed that anacardic acid 9, the most active compound, does not interact with the anti-apoptotic proteins Bcl-xL and Mcl-1 but instead interacts with pro-apoptotic protein Bid.

Fulltext Quorum Sensing Inhibitory Activity of Giganteone A from Myristica cinnamomea King against Escherichia coli Biosensors

Sivasothy Y, Krishnan T, Chan KG, Abdul Wahab SM, Othman MA, Litaudon M, et al.

Molecules, 2016 Mar 21;21(3):391.

PMID: 27102164 DOI: 10.3390/molecules21030391

Malabaricones A-C (1-3) and giganteone A (4) were isolated from the bark of Myristica cinnamomea King. Their structures were elucidated and characterized by means of NMR and MS spectral analyses. These isolates were evaluated for their anti-quorum sensing activity using quorum sensing biosensors, namely Escherichia coli [pSB401] and Escherichia coli [pSB1075], whereby the potential of giganteone A (4) as a suitable anti-quorum sensing agent was demonstrated.

Fulltext Hyaluronidase Inhibitory Activity of Pentacylic Triterpenoids from Prismatomeris tetrandra (Roxb.) K. Schum: Isolation, Synthesis and QSAR Study

Abdullah NH, Thomas NF, Sivasothy Y, Lee VS, Liew SY, Noorbatcha IA, et al.

Int J Mol Sci, 2016 Feb 14;17(2):143.

PMID: 26907251 DOI: 10.3390/ijms17020143

The mammalian hyaluronidase degrades hyaluronic acid by the cleavage of the β-1,4-glycosidic bond furnishing a tetrasaccharide molecule as the main product which is a highly angiogenic and potent inducer of inflammatory cytokines. Ursolic acid 1, isolated from Prismatomeris tetrandra, was identified as having the potential to develop inhibitors of hyaluronidase. A series of ursolic acid analogues were either synthesized via structure modification of ursolic acid 1 or commercially obtained. The evaluation of the inhibitory activity of these compounds on the hyaluronidase enzyme was conducted. Several structural, topological and quantum chemical descriptors for these compounds were calculated using semi empirical quantum chemical methods. A quantitative structure activity relationship study (QSAR) was performed to correlate these descriptors with the hyaluronidase inhibitory activity. The statistical characteristics provided by the best multi linear model (BML) (R² = 0.9717, R²cv = 0.9506) indicated satisfactory stability and predictive ability of the developed model. The in silico molecular docking study which was used to determine the binding interactions revealed that the ursolic acid analog 22 had a strong affinity towards human hyaluronidase.

Kingianins O-Q: Pentacyclic polyketides from Endiandra kingiana as inhibitor of Mcl-1/Bid interaction

Azmi MN, Péresse T, Remeur C, Chan G, Roussi F, Litaudon M, et al.

Fitoterapia, 2016 Mar;109:190-5.

PMID: 26779944 DOI: 10.1016/j.fitote.2016.01.004

A phytochemical study of the EtOAc-soluble part of the methanolic extract of the bark of Endiandra kingiana led to the isolation of three new pentacyclic kingianins as racemic mixtures, kingianins O-Q (1-3), together with the known kingianins A, F, K, L, M and N (4-9), respectively. The structures of the new kingianins 1-3 were determined by 1D and 2D NMR analysis in combination with HRESIMS experiments. Kingianins A-Q were assayed for Mcl-1 binding affinity. Kingianins G and H were found to be potent inhibitors of Mcl-1/Bid interaction. A structure-activity relationship study showed that potency is very sensitive to the substitution pattern on the pentacyclic core. In addition, in contrast with the binding affinity for Bcl-xL, the levorotatory enantiomers of kingianins G, H and J exhibited similar binding affinities for Mcl-1 than their dextrorotatory counterparts, indicating that the two anti-apoptotic proteins have slightly different binding profiles.

Fulltext Ultraviolet-visible study on acid-base equilibria of aporphine alkaloids with antiplasmodial and antioxidant activities from Alseodaphne corneri and Dehaasia longipedicellata

Zahari A, Ablat A, Omer N, Nafiah MA, Sivasothy Y, Mohamad J, et al.

Sci Rep, 2016;6:21517.

PMID: 26898753 DOI: 10.1038/srep21517

The UV-vis spectra of isocorydine 1, norisocorydine 2 and boldine 3 were studied in 2% v/v acetonitrile, at constant ionic strength (0.1 M NaCl, 35 degree Celsius). The pK(a) values of isocorydine 1 and norisocorydine 2 were 11.75 and 12.07, respectively. Boldine 3 gave a pK(a) value of 9.16 and 10.44. All of the alkaloids 1-3 were stable at physiological pH; thereby all of them will not ionize, thus permitting the basic nitrogen to be protonated and accumulated within the acidic food vacuole of Plasmodium via pH trapping. Subsequently, acidic food vacuoles that have been neutralized by alkaloids would result in enhancement of the antiplasmodial activity. The alkaloids showed antiplasmodial activity against Plasmodium falciparum and antioxidant activities; DPPH radical scavenging, metal chelating and ferric reducing power. The antioxidant properties of the alkaloids under investigation revealed that in addition to the antiplasmodial activity, the alkaloids can also prevent oxidative damage. It can be prevented by binding free heme and neutralizing the electrons produced during the Plasmodium falciparum mediated haemoglobin destruction in the host. Slightly basic properties of the aforementioned alkaloids, along with their antioxidant activities, are advantageous in improving the suppression of malaria infection that cause less damage to the host.

Venuloxanthone, a new pyranoxanthone from the stem bark of Calophyllum venulosum

Bin Ismail AA, Ee GC, Bin Daud S, Teh SS, Hashim NM, Awang K

J Asian Nat Prod Res, 2015;17(11):1104-8.

PMID: 26023810 DOI: 10.1080/10286020.2015.1047353

A new pyranoxanthone, venuloxanthone (1), was isolated from the stem bark of Calophyllum venulosum, together with three other xanthones, tovopyrifolin C (2), ananixanthone (3) and caloxanthone I (4), along with two common triterpenes, friedelin (5) and lupeol (6). The structures of these compounds were identified using several spectroscopic analyses which are NMR, GCMS and FTIR experiments.

Phoebegrandine C, a novel proaporphine-tryptamine dimer, from Phoebe grandis (Nees) Merr

Mukhtar MR, Hadi AH, Sévenet T, Martin MT, Awang K

Nat Prod Res, 2004 Apr;18(2):163-7.

PMID: 14984091

A novel proaporphine-tryptamine dimer alkaloid, named phoebegrandine C 1, was isolated from the leaves of Phoebe grandis (Nees) Merr. Its structural elucidation was carried out using spectroscopic techniques, notably 2D NMR.

Malabaricone C as Natural Sphingomyelin Synthase Inhibitor against Diet-Induced Obesity and Its Lipid Metabolism in Mice

Othman MA, Yuyama K, Murai Y, Igarashi Y, Mikami D, Sivasothy Y, et al.

ACS Med Chem Lett, 2019 Aug 08;10(8):1154-1158.

PMID: 31413799 DOI: 10.1021/acsmedchemlett.9b00171

The interaction between natural occurring inhibitors and targeted membrane proteins could be an alternative medicinal strategy for the treatment of metabolic syndrome, notably, obesity. In this study, we identified malabaricones A-C and E (1-4) isolated from the fruits of Myristica cinnamomea King as natural inhibitors for sphingomyelin synthase (SMS), a membrane protein responsible for sphingolipid biosynthesis. Having the most promising inhibition, oral administration of compound 3 exhibited multiple efficacies in reducing weight gain, improving glucose tolerance, and reducing hepatic steatosis in high fat diet-induced obesity mice models. Liver lipid analysis revealed a crucial link between the SMS activities of compound 3 and its lipid metabolism in vitro and in vivo. The nontoxic nature of compound 3 makes it a suitable candidate in search of drugs which can be employed in the treatment and prevention of obesity.

Cytotoxic constituent of Melicope latifolia (DC.) T. G. Hartley

Lim PC, Ali Z, Khan IA, Khan SI, Kassim NK, Awang K, et al.

Nat Prod Res, 2021 Feb 12.

PMID: 33576269 DOI: 10.1080/14786419.2021.1885031

An undescribed conjugated sesquiterpene, amelicarin (1), together with nine known compounds (2-10) were isolated for the first time from Melicope latifolia. Their structures were elucidated by extensive NMR spectroscopic and mass spectrometric methods. The conjugated sesquiterpene possesses a unique 6/6/9/4-ring fused tetracyclic skeleton. The proposed biosynthesis pathway of 1 consist of three reactions steps: (1) polyketide formation, (2) cyclisation and (3) addition to form the conjugated sesquiterpenoid as final metabolite. Out of the ten isolated metabolites, amelicarin (1) showed activity against 4 cancerous cell lines namely SK-MEL skin cancer, KB oral cancer, BT-549 breast cancer, and SK-OV-3 ovarian cancer with IC50 values between 15 and 25 µg/mL.

Giganteone A and malabaricone C as potential pharmacotherapy for diabetes mellitus

Sivasothy Y, Leong KH, Loo KY, Adbul Wahab SM, Othman MA, Awang K

Nat Prod Res, 2021 Feb 16.

PMID: 33593208 DOI: 10.1080/14786419.2021.1885405

The use of antidiabetic agents which control glycemic levels in the blood and simultaneously inhibit oxidative stress is an important strategy in the prevention of Diabetes Mellitus and its complications. In our previous study, malabaricone C (3) and its dimer, giganteone A (5) exhibited significant DPPH free radical scavenging activities which were lower than the activity of the positive control, ascorbic acid. These compounds were evaluated for their α-glucosidase inhibitory activities at different concentrations (0.02-2.5 mM) in the present study. Compounds 3 (IC50 59.61 µM) and 5 (IC50 39.52 µM) were identified as active alpha-glucosidase inhibitors, each respectively being 24 and 37 folds more potent than the standard inhibitor, acarbose. Based on the molecular docking studies, compounds 3 and 5 docked into the active site of the α-glucosidase enzyme, forming mainly hydrogen bonds in the active site.

Natural cholinesterase inhibitors from Myristica cinnamomea King

Abdul Wahab SM, Sivasothy Y, Liew SY, Litaudon M, Mohamad J, Awang K

Bioorg Med Chem Lett, 2016 08 01;26(15):3785-92.

PMID: 27236720 DOI: 10.1016/j.bmcl.2016.05.046

A new acylphenol, malabaricone E (1) together with the known malabaricones A-C (2-4), maingayones A and B (5 and 6) and maingayic acid B (7) were isolated from the ethyl acetate extract of the fruits of Myristica cinnamomea King. Their structures were determined by 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Compounds 3 (1.84±0.19 and 1.76±0.21μM, respectively) and 4 (1.94±0.27 and 2.80±0.49μM, respectively) were identified as dual inhibitors, with almost equal acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibiting potentials. The Lineweaver-Burk plots of compounds 3 and 4 indicated that they were mixed-mode inhibitors. Based on the molecular docking studies, compounds 3 and 4 interacted with the peripheral anionic site (PAS), the catalytic triad and the oxyanion hole of the AChE. As for the BChE, while compound 3 interacted with the PAS, the catalytic triad and the oxyanion hole, compound 4 only interacted with the catalytic triad and the oxyanion hole.

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