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Cytotoxic triterpenoids from the stem bark of Aglaia angustifolia

Hutagaol RP, Harneti D, Safari A, Hidayat AT, Supratman U, Awang K, et al.

J Asian Nat Prod Res, 2021 Aug;23(8):781-788.
PMID: 32536210 DOI: 10.1080/10286020.2020.1776704

A seco-apotirucallane-type triterpenoid, namely angustifolianin (1), along with three dammarane-type triterpenoids, (20S, 24S)-epoxy-dammarane-3β,25-diol (2), 3-epi-cabraleahydroxylactone (3), and cabralealactone (4), were isolated from the stem bark of Aglaia angustifolia Miq. The Chemical structure of the new compounds was elucidated on the basis of spectroscopic data. All of the compounds were evaluated for their cytotoxic effects against MCF-7 breast cancer cells. Among those compounds, angustifolianin (1) showed strongest cytotoxic activity with an IC50 value of 50.5 μg/ml.
Fulltext Chemicals Constituents Isolated from Cultivate Alpinia conchigera Griff. and Antimicrobial Activity

Taib MNAM, Anuar N, Hanafiah KM, Al-Shammary AAK, Saaid M, Awang K

Trop Life Sci Res, 2020 Apr;31(1):159-178.
PMID: 32963717 DOI: 10.21315/tlsr2020.31.1.10

Alpinia conchigera Griff. is a plant species from the family Zingiberaceae. Coloquially known as wild ginger, Alpinia conchigera Griff. is used as food condiment and for traditional treatment of skin diseases. Isolation studies to identify bioactive compounds of rhizomes of Alpinia conchigera yielded seven compounds; 1'S-1'-acetoxychavicol acetate (1), trans-p-coumaryl diacetate (2), p-hydroxycinnamyl acetate (3), 1'S-1'-hydroxychavicol acetate (4) p-hydroxybenzaldehyde (5), stigmasterol (6) and β-sitosterol (7). Compounds 1, 2 and 5 were evaluated for antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). Among the compounds tested, Compound 1 showed good antimicrobial activity against the strain of MRSA with minimum inhibition concentration (MIC) value of 0.5 mg/mL. Meanwhile, Compounds 2 and 5 exhibited moderate activity with MIC value between 1.0 and 2.0 mg/mL. These findings indicate antimicrobial potential of 1'S-1'-acetoxychavicol acetate (1), compound derived from rhizome of Alpinia conchigera Griff. against MRSA, which warrant further investigation.
Fulltext In vitro antiplasmodial activity, macronutrients and trace metals in the medicinal plants: Phyllanthus spp. and Alpinia conchigera Griff

Haslinda MS, Aiyub Z, Bakar NK, Tohar N, Musa Y, Abdullah NR, et al.

Trop Biomed, 2015 Mar;32(1):129-39.
PMID: 25801263

An antiplasmodial screening of Phyllanthus debilis and Phyllanthus urinaria was carried out. The medicinal plants were extracted and evaluated for in vitro antiplasmodial activity against D10 (chloroquine-sensitive, CQS) and Gombak A (chloroquine-resistant, CQR) strains of Plasmodium falciparum. The methanolic crudes from the soxhlet extraction were active against both strains however, P. urinaria (IC50 8.9 μg/ml with CQR strain) exhibited better anti-malarial activity compared to P. debilis (IC50 12.2 μg/ml with CQR strain). Furthermore, the methanolic crude of P. urinaria obtained by the cold extraction has good anti-malarial activity towards CQS (IC50 4.1 μg/ml). The concentration of macronutrients (calcium and magnesium) and trace metals (copper, manganese, iron and zinc) from three Phyllanthus species i.e. P. debilis Klein ex Wild., Phyllanthus niruri L., P. urinaria L. and Alpinia conchigera Griff. were determined using microwave digestion method and analyzed by Flame Atomic Absorption Spectroscopy. Standard Reference Material 1547 (peach leaves) was used to validate the method throughout this study. The recovery values were in the range of 80% to 120% which were in very good agreement with the certified values. The three Phyllanthus species and leaves of A. conchigera showed the highest concentration of calcium compared to other metals and macronutrients studied. The significant presence of all the important macronutrients and trace metals which are essential for human health and well-being substantiate their use medicinally in traditional practices.
Natural DENV-2 NS2B/NS3 protease inhibitors from Myristica cinnamomea King

Sivasothy Y, Liew SY, Othman MA, Abdul Wahab SM, Hariono M, Mohd Nawi MS, et al.

Trop Biomed, 2021 Jun 01;38(2):79-84.
PMID: 33973577 DOI: 10.47665/tb.38.2.044

The NS2B/NS3 protease is crucial for the pathogenesis of the DENV. Therefore, the inhibition of this protease is considered to be the key strategy for the development of new antiviral drugs. In the present study, malabaricones C (3) and E (4), acylphenols from the fruits of Myristica cinnamomea King, have been respectively identified as moderate (27.33 ± 5.45 μM) and potent (7.55 ± 1.64 μM) DENV-2 NS2B/NS3 protease inhibitors, thus making this the first report on the DENV-2 NS2B/NS3 protease inhibitory activity of acylphenols. Based on the molecular docking studies, compounds 3 and 4 both have π-π interactions with Tyr161. While compound 3 has hydrogen bonding interactions with Gly151, Gly153 and Tyr161, compound 4 however, forms hydrogen bonds with Ser135, Asp129, Phe130 and Ile86 instead. The results from the present study suggests that malabaricones C (3) and E (4) could be employed as lead compounds for the development of new dengue antivirals from natural origin.
Fulltext The apoptotic effect of 1'S-1'-Acetoxychavicol Acetate (ACA) enhanced by inhibition of non-canonical autophagy in human non-small cell lung cancer cells

Sok SP, Arshad NM, Azmi MN, Awang K, Ozpolat B, Hasima Nagoor N

PLoS One, 2017;12(2):e0171329.
PMID: 28158287 DOI: 10.1371/journal.pone.0171329

Autophagy plays a role in deciding the fate of cells by inducing either survival or death. 1'S-1-acetoxychavicol acetate (ACA) is a phenylpropanoid isolated from rhizomes of Alpinia conchigera and has been reported previously on its apoptotic effects on various cancers. However, the effect of ACA on autophagy remains ambiguous. The aims of this study were to investigate the autophagy-inducing ability of ACA in human non-small cell lung cancer (NSCLC), and to determine its role as pro-survival or pro-death mechanism. Cell viability assay was conducted using MTT. The effect of autophagy was assessed by acridine orange staining, GFP-LC3 punctate formation assay, and protein level were analysed using western blot. Annexin V-FITC/PI staining was performed to detect percentage of cells undergoing apoptosis by using flow cytometry. ACA inhibits the cell viability and induced formation of cytoplasmic vacuoles in NSCLC cells. Acidic vesicular organelles and GFP-LC3 punctate formation were increased in response to ACA exposure in A549 and SK-LU-1 cell lines; implying occurrence of autophagy. In western blot, accumulation of LC3-II accompanied by degradation of p62 was observed, which further confirmed the full flux of autophagy induction by ACA. The reduction of Beclin-1 upon ACA treatment indicated the Beclin-1-independent autophagy pathway. An early autophagy inhibitor, 3-methyaldenine (3-MA), failed to suppress the autophagy triggered by ACA; validating the existence of Beclin-1-independent autophagy. Silencing of LC3-II using short interfering RNA (siRNA) abolished the autophagy effects, enhancing the cytotoxicity of ACA through apoptosis. This proposed ACA triggered a pro-survival autophagy in NSCLC cells. Consistently, co-treatment with lysosomal inhibitor, chloroquine (CQ), exerted a synergistic effect resulting in apoptosis. Our findings suggested ACA induced pro-survival autophagy through Beclin-1-independent pathway in NSCLC. Hence, targeting autophagy pathway using autophagy inhibitor such as CQ represented a novel promising approach to potentiate the cytotoxicity of ACA through apoptosis in NSCLC.
Induction of intrinsic apoptosis in leukaemia stem cells and in vivo zebrafish model by betulonic acid isolated from Walsura pinnata Hassk (Meliaceae)

Leong KH, Mahdzir MA, Din MF, Awang K, Tanaka Y, Kulkeaw K, et al.

Phytomedicine, 2017 Mar 15;26:11-21.
PMID: 28257660 DOI: 10.1016/j.phymed.2016.12.018

BACKGROUND: Leukaemia stem cells (LSC) have been associated with disease relapse and chemotherapy resistance. Betulonic acid (BA), a pentacyclic lupane-type triterpenoid, was reported to exhibit cytotoxicity toward various cancer cells and to be capable of inducing intrinsic apoptosis in solid tumours. However, the in vitro and in vivo apoptotic effects of BA against LSC remain unknown.
HYPOTHESIS/PURPOSE: We aimed to determine whether BA isolated from bark of Walsura pinnata Hassk (Meliaceae) has pro-apoptotic effects on LSC in in vitro and in vivo models.
STUDY DESIGN/METHODS: The population of high purity LSC was isolated from the Kasumi-1 cell line using magnetic sorting and characterised by flow cytometry. Cell viability was assessed using the MTS assay to examine dose- and time-dependent effects. The colony formation assay was performed in MethoCult® H4435 enriched media. Apoptosis was analysed using Annexin-V and propidium iodide staining, mitochondrial transmembrane potential was studied using JC-1 staining, and expression of apoptosis related genes (BAX, Bcl-2 and survivin) was evaluated by real time-polymerase chain reaction (RT-PCR). Caspase 3/7 and 9 activities were monitored through Promega Caspase-Glo® over a period of 24h. The in vivo antileukaemia activity was evaluated using LSC xenotransplanted zebrafish, observed for DNA fragmentation from apoptosis by TUNEL assay.
RESULTS: BA maintained its potency against the LSC population in comparison to parental Kasumi-1 cells (fold differences ≤ 1.94) over various treatment time points and significantly inhibited the formation of colonies by LSC. Apoptosis was triggered by BA through the upregulation of BAX and suppression of Bcl-2 and survivin genes with the loss of mitochondrial transmembrane potential, leading to the activation of caspase 9 followed by downstream caspase 3/7. BA was able to suppressed leukaemia formation and induced apoptosis in LSC xenotransplanted zebrafish.
CONCLUSIONS: The results demonstrate that BA inhibited the proliferative and colonogenic properties of LSC. BA induced apoptosis in LSC through the mitochondria pathway and was effective in the in vivo zebrafish model. Therefore, BA could be a lead compound for further development into a chemotherapy agent against LSC.
Fulltext Inactivation of nuclear factor κB by MIP-based drug combinations augments cell death of breast cancer cells

Subramaniam M, Liew SK, In L, Awang K, Ahmed N, Nagoor NH

Drug Des Devel Ther, 2018;12:1053-1063.
PMID: 29750018 DOI: 10.2147/DDDT.S141925

Background: Drug combination therapy to treat cancer is a strategic approach to increase successful treatment rate. Optimizing combination regimens is vital to increase therapeutic efficacy with minimal side effects.
Materials and methods: In the present study, we evaluated the in vitro cytotoxicity of double and triple combinations consisting of 1'S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP) and cisplatin (CDDP) against 14 various human cancer cell lines to address the need for more effective therapy. Our data show synergistic effects in MCF-7 cells treated with MIP:ACA, MIP:CDDP and MIP:ACA:CDDP combinations. The type of interaction between MIP, ACA and CDDP was evaluated based on combination index being <0.8 for synergistic effect. Identifying the mechanism of cell death based on previous studies involved intrinsic apoptosis and nuclear factor kappa B (NF-κB) and tested in Western blot analysis. Inactivation of NF-κB was confirmed by p65 and IκBα, while intrinsic apoptosis pathway activation was confirmed by caspase-9 and Apaf-1 expression.
Results: All combinations confirmed intrinsic apoptosis activation and NF-κB inactivation.
Conclusion: Double and triple combination regimens that target induction of the same death mechanism with reduced dosage of each drug could potentially be clinically beneficial in reducing dose-related toxicities.
Resveratrol analogue, (E)-N-(2-(4-methoxystyryl) phenyl) furan-2-carboxamide induces G2/M cell cycle arrest through the activation of p53-p21CIP1/WAF1 in human colorectal HCT116 cells

Cheah FK, Leong KH, Thomas NF, Chin HK, Ariffin A, Awang K

Apoptosis, 2018 Jun;23(5-6):329-342.
PMID: 29754265 DOI: 10.1007/s10495-018-1457-8

Resveratrol, a naturally occurring polyphenolic antioxidant, is a potential chemoprophylactic agent for various cancers, including colorectal cancer. Although emerging evidence continually suggests that a number of resveratrol derivatives may be better cancer chemopreventive candidates than resveratrol, studies on the mechanism of action of these derivatives are limited. This is the first study which investigates the mechanism underlying the cytotoxic effect of a synthesized resveratrol analogue, (E)-N-(2-(4-methoxystyryl) phenyl) furan-2-carboxamide (CS) on colorectal cancer. Previously, our group reported a series of synthesized resveratrol analogues, which showed cytotoxicity against a panel of cancer cell lines, in particular on colon cancer cells. In this study, we further discovered that CS also exerts a potent suppressive effect on HCT116 colorectal cancer cells. In contrast, normal colon cells (CCD-112 Con) were not sensitive to CS up to 72 h post treatment. CS caused cytotoxicity in HCT116 cells through several apoptotic events including activation of the Fas death receptor, FADD, caspase 8, caspase 3, caspase 9, and cleaved PARP, which occurred alongside cell cycle arrest from the up-regulation of p53 and p21. The results show that CS causes apoptosis via the activation of an extrinsic pathway leading to caspase activation and cell cycle arrest from activated p53. These findings suggest that CS may be a potential candidate for development as an anti-tumor agent in the future.
In vitro inhibitory mechanisms and molecular docking of 1'-S-1'-acetoxychavicol acetate on human cytochrome P450 enzymes

Haque AKMM, Leong KH, Lo YL, Awang K, Nagoor NH

Phytomedicine, 2017 Jul 15;31:1-9.
PMID: 28606510 DOI: 10.1016/j.phymed.2017.05.002

BACKGROUND: The compound, 1'-S-1'-acetoxychavicol acetate (ACA), isolated from the rhizomes of a Malaysian ethno-medicinal plant, Alpinia conchigera Griff. (Zingiberaceae), was previously shown to have potential in vivo antitumour activities. In the development of a new drug entity, potential interactions of the compound with the cytochrome P450 superfamily metabolizing enzymes need to be ascertain.
PURPOSE: The concomitant use of therapeutic drugs may cause potential drug-drug interactions by decreasing or increasing plasma levels of the administered drugs, leading to a suboptimal clinical efficacy or a higher risk of toxicity. Thus, evaluating the inhibitory potential of a new chemical entity, and to clarify the mechanism of inhibition and kinetics in the various CYP enzymes is an important step to predict drug-drug interactions.
STUDY DESIGN: This study was designed to assess the potential inhibitory effects of Alpinia conchigera Griff. rhizomes extract and its active constituent, ACA, on nine c-DNA expressed human cytochrome P450s (CYPs) enzymes using fluorescent CYP inhibition assay.
METHODS/RESULTS: The half maximal inhibitory concentration (IC50) of Alpinia conchigera Griff. rhizomes extract and ACA was determined for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. A. conchigera extract only moderately inhibits on CYP3A4 (IC50 = 6.76 ± 1.88µg/ml) whereas ACA moderately inhibits the activities of CYP1A2 (IC50 = 4.50 ± 0.10µM), CYP2D6 (IC50 = 7.50 ± 0.17µM) and CYP3A4 (IC50 = 9.50 ± 0.57µM) while other isoenzymes are weakly inhibited. In addition, mechanism-based inhibition studies reveal that CYP1A2 and CYP3A4 exhibited non-mechanism based inhibition whereas CYP2D6 showed mechanism-based inhibition. Lineweaver-Burk plots depict that ACA competitively inhibited both CYP1A2 and CYP3A4, with a Ki values of 2.36 ± 0.03 µM and 5.55 ± 0.06µM, respectively, and mixed inhibition towards CYP2D6 with a Ki value of 4.50 ± 0.08µM. Further, molecular docking studies show that ACA is bound to a few key amino acid residues in the active sites of CYP1A2 and CYP3A4, while one amino residue of CYP2D6 through predominantly Pi-Pi interactions.
CONCLUSION: Overall, ACA may demonstrate drug-drug interactions when co-administered with other therapeutic drugs that are metabolized by CYP1A2, CYP2D6 or CYP3A4 enzymes. Further in vivo studies, however, are needed to evaluate the clinical significance of these interactions.
Fulltext Cytotoxic Effects of Pinnatane A Extracted from Walsura pinnata (Meliaceae) on Human Liver Cancer Cells

Zakaria N, Mahdzir MA, Yusoff M, Mohd Arshad N, Awang K, Nagoor NH

Molecules, 2018 Oct 23;23(11).
PMID: 30360475 DOI: 10.3390/molecules23112733

BACKGROUND: Pinnatane A from the bark of Walsura pinnata was investigated for its anti-cancer properties by analyzing the cytotoxic activities and cell cycle arrest mechanism induced in two different liver cancer cell lines.
METHODS: A 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to analyze the pinnatane A selectivity in inducing cell death in cancer and normal cells. Various biological assays were carried out to analyze the anti-cancer properties of pinnatane A, such as a live/dead assay for cell death microscopic visualization, cell cycle analysis using propidium iodide (PI) to identify the cell cycle arrest phase, annexin V-fluorescein isothiocyanate (annexin V-FITC)/PI flow cytometry assay to measure percentage of cell populations at different stages of apoptosis and necrosis, and DNA fragmentation assay to verify the late stage of apoptosis.
RESULTS: The MTT assay identified pinnatane A prominent dose- and time-dependent cytotoxicity effects in Hep3B and HepG2 cells, with minimal effect on normal cells. The live/dead assay showed significant cell death, while cell cycle analysis showed arrest at the G₀/G₁ phase in both cell lines. Annexin V-FITC/PI flow cytometry and DNA fragmentation assays identified apoptotic cell death in Hep3B and necrotic cell death in HepG2 cell lines.
CONCLUSIONS: Pinnatane A has the potential for further development as a chemotherapeutic agent prominently against human liver cells.
Acute and 28-day sub-acute intravenous toxicity studies of 1'-S-1'-acetoxychavicol acetate in rats

Abdalla YOA, Nyamathulla S, Shamsuddin N, Arshad NM, Mun KS, Awang K, et al.

Toxicol Appl Pharmacol, 2018 10 01;356:204-213.
PMID: 30138658 DOI: 10.1016/j.taap.2018.08.014

1'-S-1'-acetoxychavicol acetate (ACA) has been previously reported to reduce tumor volume in nude mice, at an effective dose of 1.56 mg/kg body weight. However, the detailed toxicological profile for ACA has not yet been performed. Herein, we investigated the toxicity of intravenous administration of ACA in male and female Sprague-Dawley rats, both acutely (with single doses of 2.00, 4.00 and 6.66 mg/kg body weight, for 14 days), and sub-acutely (with weekly injections of 0.66, 1.33, and 2.22 mg/kg, for 28 days). In both toxicity studies, treatment with ACA did not affect behavior, food/water intake or body weight, nor did it induce any changes in clinically relevant hematological and biochemical parameters or mortality, suggesting that the LD50 of ACA was higher than 6.66 mg/kg body weight, regardless of sex. Sub-acutely, there was however, mild focal inflammation of kidneys and lobular hepatitis, but these were not associated with significant functional adverse effects. Therefore, the no-observed-adverse-effect level (NOAEL) for intravenous administration of ACA in the present 28-day sub-acute study was 2.22 mg/kg body weight, in both male and female rats. These findings provide useful information regarding the safety of ACA use in a healthy, non-tumor-bearing rat model.
Fulltext Anti-Cancer Effects of Synergistic Drug-Bacterium Combinations on Induced Breast Cancer in BALB/c Mice

Subramaniam M, Arshad NM, Mun KS, Malagobadan S, Awang K, Nagoor NH

Biomolecules, 2019 10 18;9(10).
PMID: 31635311 DOI: 10.3390/biom9100626

Cancer development and progression are extremely complex due to the alteration of various genes and pathways. In most cases, multiple agents are required to control cancer progression. The purpose of this study is to investigate, using a mouse model, the synergistic interactions of anti-cancer agents, 1'-S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP), and cisplatin (CDDP) in double and triple combinations to treat chemo-sensitize and immune-sensitize breast cancer. Changes in tumor volume and body weight were monitored. Organs were harvested and stained using hematoxylin-eosin for histopathological assessment. Milliplex enzyme-linked immunosorbent assay (ELISA) was performed to determine cytokine levels, while immunohistochemistry (IHC) was conducted on tumor biopsies to verify systemic drug effects. In vivo mouse models showed tumor regression with maintenance of regular body weight for all the different treatment regimens. IHC results provided conclusive evidence indicating that combination regimens were able to down-regulate nuclear factor kappa-B activation and reduce the expression of its regulated pro-inflammatory proteins. Reduction of pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IFN-ɣ) levels were observed when using the triple combination, which indicated that the synergistic drug combination was able to significantly control cancer progression. In conclusion, ACA, MIP, and CDDP together serve as promising candidates for further development and for subsequent clinical trials against estrogen-sensitive breast cancer.
Absolute Configuration of Alkaloids from Uncaria longiflora through Experimental and Computational Approaches

Salim F, Yunus YM, Anouar EH, Awang K, Langat M, Cordell GA, et al.

J Nat Prod, 2019 11 22;82(11):2933-2940.
PMID: 31686505 DOI: 10.1021/acs.jnatprod.8b00380

The structure elucidation of three new alkaloids named isoformosaninol (1), formosaninol (2), and longiflorine (3), isolated from the leaves of Uncaria longiflora var. pteropoda (Miq.) Ridsdale, along with their biosynthetic pathways are discussed. Their absolute structures were determined through a combination of physical data interpretation and quantum chemical calculations using the time-dependent density functional theory (TDDFT) method.
Fulltext Oxygen radical antioxidant capacity (ORAC) and antibacterial properties of Melicope glabra bark extracts and isolated compounds

Quek A, Mohd Zaini H, Kassim NK, Sulaiman F, Rukayadi Y, Ismail A, et al.

PLoS One, 2021;16(5):e0251534.
PMID: 33970960 DOI: 10.1371/journal.pone.0251534

Melicope glabra (Blume) T. G. Hartley from the Rutaceae family is one of the richest sources of plant secondary metabolites, including coumarins and flavanoids. This study investigates the free radical scavenging and antibacterial activities of M. glabra and its isolated compounds. M. glabra ethyl acetate and methanol extracts were prepared using the cold maceration technique. The isolation of compounds was performed with column chromatography. The free radical scavenging activity of the extracts and isolated compounds were evaluated based on their oxygen radical absorbance capacity (ORAC) activities. The extracts and compounds were also subjected to antibacterial evaluation using bio-autographic and minimal inhibitory concentration (MIC) techniques against two oral pathogens, Enterococcus faecalis and Streptococcus mutans. Isolation of phytoconstituents from ethyl acetate extract successfully yielded quercetin 3, 5, 3'-trimethyl ether (1) and kumatakenin (2), while the isolation of the methanol extract resulted in scoparone (3), 6, 7, 8-trimethoxycoumarin (4), marmesin (5), glabranin (6), umbelliferone (7), scopoletin (8), and sesamin (9). The study is the first to isolate compound (1) from Rutaceae plants, and also the first to report the isolation of compounds (2-5) from M. glabra. The ORAC evaluation showed that the methanol extract is stronger than the ethyl acetate extract, while umbelliferone (7) exhibited the highest ORAC value of 24 965 μmolTE/g followed by glabranin (6), sesamin (9) and scopoletin (8). Ethyl acetate extract showed stronger antibacterial activity towards E. faecalis and S. mutans than the methanol extract with MIC values of 4166.7 ± 1443.4 μg/ml and 8303.3 ± 360.8 μg/ml respectively. Ethyl acetate extract inhibited E. faecalis growth, as shown by the lowest optical density value of 0.046 at a concentration of 5.0 mg/mL with a percentage inhibition of 95%. Among the isolated compounds tested, umbelliferone (7) and sesamin (9) exhibited promising antibacterial activity against S. mutans with both exhibiting MIC values of 208.3 ± 90.6 μg/ml. Findings from this study suggests M. glabra as a natural source of potent antioxidant and antibacterial agents.
Cytototoxic constituents from the bark of Chisocheton cumingianus (Meliaceae)

Katja DG, Farabi K, Nurlelasari, Harneti D, Mayanti T, Supratman U, et al.

J Asian Nat Prod Res, 2016 Jun 22.
PMID: 27329305 DOI: 10.1080/10286020.2016.1196671

A new lanostane-type triterpenoid, 3β-hydroxy-25-ethyl-lanost-9(11),24(24')-diene (1), along with 3β-hydroxy-lanost-7-ene (2) and β-sitosterol-3-O-acetate (3) was isolated from the stem bark of C. cumingianus. The chemical structure of the new compound was elucidated on the basis of spectroscopic data. All of the compounds were evaluated for their cytotoxic effects against P-388 murine leukemia cells. Compounds 1-3 showed cytotoxicity against P-388 murine leukemia cells with IC50 values of 28.8 ± 0.10, 4.29 ± 0.03, and 100.18 ± 0.16 μg/ml, respectively.
Chemical constituents and antimicrobial activity of the leaf and rhizome oils of Alpinia pahangensis Ridl., an endemic wild ginger from peninsular Malaysia

Awang K, Ibrahim H, Rosmy Syamsir D, Mohtar M, Mat Ali R, Azah Mohamad Ali N

Chem Biodivers, 2011 Apr;8(4):668-73.
PMID: 21480512 DOI: 10.1002/cbdv.201000225

The essential oils from the leaves and rhizomes of Alpinia pahangensis Ridl., collected from Pahang, Peninsular Malaysia, were obtained by hydrodistillation, and their chemical compositions were determined by GC and GC/MS analyses. The major components of the rhizome oil were γ-selinene (11.60%), β-pinene (10.87%), (E,E)-farnesyl acetate (8.65%), and α-terpineol (6.38%), while those of the leaf oil were β-pinene (39.61%), α-pinene (7.55%), and limonene (4.89%). The investigation of the antimicrobial activity of the essential oils using the broth microdilution technique revealed that the rhizome oil of A. pahangensis inhibited five Staphylococcus aureus strains with minimum inhibitory concentration (MIC) values between 0.08 and 0.31 μg/μl, and four selected fungi with MIC values between 1.25 and 2.50 μg/μl.
Advances in Chemistry and Bioactivity of the Genus Chisocheton Blume

Shilpi JA, Saha S, Chong SL, Nahar L, Sarker SD, Awang K

Chem Biodivers, 2016 May;13(5):483-503.
PMID: 26970405 DOI: 10.1002/cbdv.201400373

Chisocheton is one of the genera of the family Meliaceae and consists of ca. 53 species; the distribution of most of those are confined to the Indo-Malay region. Species of broader geographic distribution have undergone extensive phytochemical investigations. Previous phytochemical investigations of this genus resulted in the isolation of mainly limonoids, apotirucallane, tirucallane, and dammarane triterpenes. Reported bioactivities of the isolated compounds include cytotoxic, anti-inflammatory, antifungal, antimalarial, antimycobacterial, antifeedant, and lipid droplet inhibitory activities. Aside from chemistry and biological activities, this review also deals briefly with botany, distribution, and uses of various species of this genus.
Antiplasmodial and antioxidant isoquinoline alkaloids from Dehaasia longipedicellata

Zahari A, Cheah FK, Mohamad J, Sulaiman SN, Litaudon M, Leong KH, et al.

Planta Med, 2014 May;80(7):599-603.
PMID: 24723007 DOI: 10.1055/s-0034-1368349

The crude extract of the bark of Dehaasia longipedicellata exhibited antiplasmodial activity against the growth of Plasmodium falciparum K1 isolate (resistant strain). Phytochemical studies of the extract led to the isolation of six alkaloids: two morphinandienones, (+)-sebiferine (1) and (-)-milonine (2); two aporphines, (-)-boldine (3) and (-)-norboldine (4); one benzlyisoquinoline, (-)-reticuline (5); and one bisbenzylisoquinoline, (-)-O-O-dimethylgrisabine (6). Their structures were determined on the basis of 1D and 2D NMR, IR, UV, and LCMS spectroscopic techniques and upon comparison with literature values. Antiplasmodial activity was determined for all of the isolated compounds. They showed potent to moderate activity with IC50 values ranging from 0.031 to 30.40 µM. (-)-O-O-dimethylgrisabine (6) and (-)-milonine (2) were the two most potent compounds, with IC50 values of 0.031 and 0.097 µM, respectively, that were comparable to the standard, chloroquine (0.090 µM). The compounds were also assessed for their antioxidant activities with di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (IC50 = 18.40-107.31 µg/mL), reducing power (27.40-87.40 %), and metal chelating (IC50 = 64.30 to 257.22 µg/mL) having good to low activity. (-)-O-O-dimethylgrisabine (6) exhibited a potent antioxidant activity of 44.3 % reducing power, while di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium and metal chelating activities had IC50 values of 18.38 and 64.30 µg/mL, respectively. Thus it may be considered as a good reductant with the ability to chelate metal and prevent pro-oxidant activity. In addition to the antiplasmodial and antioxidant activities, the isolated compounds were also tested for their cytotoxicity against a few cancer and normal cell lines. (-)-Norboldine (4) exhibited potent cytotoxicity towards pancreatic cancer cell line BxPC-3 with an IC50 value of 27.060 ± 1.037 µM, and all alkaloids showed no toxicity towards the normal pancreatic cell line (hTERT-HPNE).
A new bis-labdanic diterpene from the rhizomes of Alpinia pahangensis

Sivasothy Y, Ibrahim H, Paliany AS, Alias SA, Md Nor NR, Awang K

Planta Med, 2013 Dec;79(18):1775-80.
PMID: 24356874 DOI: 10.1055/s-0033-1351075

The rhizomes of Alpinia pahangensis yielded a new bis-labdanic diterpene for which the name pahangensin C (1) was proposed along with twelve known analogues (2-13). The structure of 1 was elucidated via spectroscopic methods including 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Compounds 2 and 12 were isolated for the first time from the genus Alpinia. This is the second occurrence of compounds 2 and 12 in the Zingiberaceae family. Selected analogues exhibited moderate to strong inhibitory activity against Staphylococcus aureus and Bacillus cereus.
Cholinesterase inhibitory activity of isoquinoline alkaloids from three Cryptocarya species (Lauraceae)

Wan Othman WNN, Liew SY, Khaw KY, Murugaiyah V, Litaudon M, Awang K

Bioorg Med Chem, 2016 09 15;24(18):4464-4469.
PMID: 27492195 DOI: 10.1016/j.bmc.2016.07.043

Alzheimer's disease is the most common form of dementia among older adults. Acetylcholinesterase and butyrylcholinesterase are two enzymes involved in the breaking down of the neurotransmitter acetylcholine. Inhibitors for these enzymes have potential to prolong the availability of acetylcholine. Hence, the search for such inhibitors especially from natural products is needed in developing potential drugs for Alzheimer's disease. The present study investigates the cholinesterase inhibitory activity of compounds isolated from three Cryptocarya species towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Nine alkaloids were isolated; (+)-nornantenine 1, (-)-desmethylsecoantofine 2, (+)-oridine 3, (+)-laurotetanine 4 from the leaves of Cryptocarya densiflora BI., atherosperminine 5, (+)-N-methylisococlaurine 6, (+)-N-methyllaurotetanine 7 from the bark of Cryptocarya infectoria Miq., 2-methoxyatherosperminine 8 and (+)-reticuline 9 from the bark of Cryptocarya griffithiana Wight. In general, most of the alkaloids showed higher inhibition towards BChE as compared to AChE. The phenanthrene type alkaloid; 2-methoxyatherosperminine 8, exhibited the most potent inhibition against BChE with IC50 value of 3.95μM. Analysis of the Lineweaver-Burk (LB) plot of BChE activity over a range of substrate concentration suggested that 2-methoxyatherosperminine 8 exhibited mixed-mode inhibition with an inhibition constant (Ki) of 6.72μM. Molecular docking studies revealed that 2-methoxyatherosperminine 8 docked well at the choline binding site and catalytic triad of hBChE (butyrylcholinesterase from Homo sapiens); hydrogen bonding with Tyr 128 and His 438 residues respectively.

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