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Gas-pressurized dispersive powder flow tester for low volume sample characterization

Majid AM, Wong TW

Int J Pharm, 2013 May 1;448(1):150-8.
PMID: 23506957 DOI: 10.1016/j.ijpharm.2013.03.008

The conventional powder flow testers require sample volumes larger than 40g and are met with experimental hiccups due to powder cohesion. This study designed a gas-pressurized dispersive powder flow tester where a high velocity air is used to disaggregate powder (9g) and eliminate its cohesion. The pressurized gas entrained solid particles leaving an orifice where the distance, surface area, width and weight of particle dispersion thereafter are determined as flow index. The flow indices of seven lactose grades with varying size, size distribution, shape, morphology, bulk and tapped densities characteristics were examined. They were compared against Hausner ratio and Carr's index parameters of the same powder mass. Both distance and surface area attributes of particle dispersion had significant negative correlations with Hausner ratio and Carr's index values of lactose. The distance, surface area and ease of particle dispersion varied proportionately with circular equivalent, surface weighted mean and volume weighted mean diameters of lactose, and inversely related to their specific surface area and elongation characteristics. Unlike insensitive Hausner ratio and Carr's index, an increase in elongation property of lactose particles was detectable through reduced powder weight loss from gas-pressurized dispersion as a result of susceptible particle blockage at orifice. The gas-pressurized dispersive tester is a useful alternative flowability measurement device for low volume and cohesive powder.
Designing the angiogenic inhibitor for brain tumor via disruption of VEGF and IL17A expression

Khan MS, Majid AM, Iqbal MA, Majid AS, Al-Mansoub M, Haque RS

Eur J Pharm Sci, 2016 Oct 10;93:304-18.
PMID: 27552907 DOI: 10.1016/j.ejps.2016.08.032

Glioblastoma multiforme is a highly malignant, heterogenic, and drug resistant tumor. The blood-brain barrier (BBB), systemic cytotoxicity, and limited specificity are the main obstacles in designing brain tumor drugs. In this study a computational approach was used to design brain tumor drugs that could downregulate VEGF and IL17A in glioblastoma multiforme type four. Computational screening tools were used to evaluate potential candidates for antiangiogenic activity, target binding, BBB permeability, and ADME physicochemical properties. Additionally, in vitro cytotoxicity, migration, invasion, tube formation, apoptosis, ROS and ELISA assays were conducted for molecule 6 that was deemed most likely to succeed. The efflux ratio of membrane permeability and calculated docking scores of permeability to glycoproteins (P-gps) were used to determine the BBB permeability of the molecules. The results showed BBB permeation for molecule 6, with the predicted efficiency of 0.55kcal/mol and binding affinity of -37kj/mol corresponding to an experimental efflux ratio of 0.625 and predicted -15kj/mol of binding affinity for P-gps. Molecule 6 significantly affected the angiogenesis pathways by 2-fold downregulation of IL17A and VEGF through inactivation of active sites of HSP90 (predicted binding: -37kj/mol, predicted efficiency: 0.55kcal/mol) and p23 (predicted binding: 12kj/mol, predicted efficiency: 0.17kcal/mol) chaperon proteins. Additionally, molecule 6 activated the 17.38% relative fold of ROS level at 18.3μg/mL and upregulated the caspase which lead the potential synergistic apoptosis through the antiangiogenic activity of molecule 6 and thereby the highly efficacious anticancer upshot. The results indicate that the binding of the molecules to the therapeutic target is not essential to produce a lethal effect on cancer cells of the brain and that antiangiogenic efficiency is much more important.
Ischemic optic neuropathy as a model of neurodegenerative disorder: A review of pathogenic mechanism of axonal degeneration and the role of neuroprotection

Khalilpour S, Latifi S, Behnammanesh G, Majid AM, Majid AS, Tamayol A

J Neurol Sci, 2017 Apr 15;375:430-441.
PMID: 28320183 DOI: 10.1016/j.jns.2016.12.044

Optic neuropathy is a neurodegenerative disease which involves optic nerve injury. It is caused by acute or intermittent insults leading to visual dysfunction. There are number of factors, responsible for optic neuropathy, and the optic nerve axon is affected in all type which causes the loss of retinal ganglion cells. In this review we will highlight various mechanisms involved in the cell loss cascades during axonal degeneration as well as ischemic optic neuropathy. These mechanisms include oxidative stress, excitotoxicity, angiogenesis, neuroinflammation and apoptosis following retinal ischemia. We will also discuss the effect of neuroprotective agents in attenuation of the negative effect of factors involve in the disease occurrence and progression.
Increased aqueous solubility and proapoptotic activity of potassium koetjapate against human colorectal cancer cells

Jafari SF, Khadeer Ahamed MB, Iqbal MA, Al Suede FS, Khalid SH, Haque RA, et al.

J Pharm Pharmacol, 2014 Oct;66(10):1394-409.
PMID: 25039905 DOI: 10.1111/jphp.12272

Recently, we have isolated koetjapic acid (KA) from Sandoricum koetjape and identified its selective anticancer potentiality against colorectal carcinoma. KA is quite likely to be useful as a systemic anticancer agent against colorectal malignancy. However, with extremely low solubility, KA has to be converted into a biocompatible solubilized form without compromising the bioefficacy. Objective of this study is to enhance solubility of KA and to evaluate anticancer efficacy of potassium koetjapate in human colorectal cancer cells.
Fulltext Synthesis, molecular structure and spectroscopic investigations of novel fluorinated spiro heterocycles

Islam MS, Al-Majid AM, Barakat A, Soliman SM, Ghabbour HA, Quah CK, et al.

Molecules, 2015 May 07;20(5):8223-41.
PMID: 25961163 DOI: 10.3390/molecules20058223

This paper describes an efficient and regioselective method for the synthesis of novel fluorinated spiro-heterocycles in excellent yield by cascade [5+1] double Michael addition reactions. The compounds 7,11-bis(4-fluorophenyl)-2,4-dimethyl- 2,4-diazaspiro[5.5] undecane-1,3,5,9-tetraone (3a) and 2,4-dimethyl-7,11-bis (4-(trifluoromethyl)phenyl)-2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraone (3b) were characterized by single-crystal X-ray diffraction, FT-IR and NMR techniques. The optimized geometrical parameters, infrared vibrational frequencies and NMR chemical shifts of the studied compounds have also been calculated using the density functional theory (DFT) method, using Becke-3-Lee-Yang-Parr functional and the 6-311G(d,p) basis set. There is good agreement between the experimentally determined structural parameters, vibrational frequencies and NMR chemical shifts of the studied compounds and those predicted theoretically. The calculated natural atomic charges using NBO method showed higher polarity of 3a compared to 3b.The calculated electronic spectra are also discussed based on the TD-DFT calculations.
Crystal Structures and Cytotoxicity of Ortho-Xylene Linked Bis-benzimidazolium Salts

Iqbal MA, Haque RA, Ahamed SA, Jafari SF, Khadeer Ahamed MB, Abdul Majid AM

Med Chem, 2015;11(5):473-81.
PMID: 25553509

Azolium (imidazolium and benzimidazolium) salts are known as stable precursors for the synthesis of Metal-N-Heterocyclic Carbene (M-NHC) complexes. Recently, some reports have been compiled indicating that benzimidazolium salts have anticarcinogenic properties. The current research is the further investigation of this phenomenon. Three ortho-xylene linked bis-benzimidazolium salts (1-3) with octyl, nonyl and decyl terminal chain lengths have been synthesized. Each of the compounds was characterized using FT-IR and NMR spectroscopic techniques. The molecular geometries of two of the salts (1-2) have been established using X-ray crystallographic technique. The compounds were tested for their cytotoxic properties against three cancerous cell lines namely, human colon cancer (HCT 116), human colorectal adenocarcinoma (HT- 29) and human breast adenocarcinoma (MCF-7). Mouse embryonic fibroblast (3T3-L1) was used as the model cell line of normal cells. The compounds showed selective anti-proliferative activities against the colorectal carcinoma cells. For HCT 116 and HT-29 cells, the IC50 values ranged 0.9-2.6 µM and 4.0-10.0 µM, respectively. The salts 1 and 3 displayed moderate cytotoxicity against the breast cancer (MCF-7) cells with IC50 58.2 and 13.3 µM, respectively. However, the salt 2 produced strong cytotoxicity against MCF-7 cells with IC50 4.4 µM. Interestingly, the compounds demonstrated poor cytotoxic effects towards the normal cells (3T3-L1) as the IC50 was found to be as high as 48.0 µM. Salts 2 and 3 demonstrated more pronounced anti-proliferative effect than the standard drugs used (5-Flourouracil and Tamoxifen).
Macrophage and colon tumor cells as targets for a binuclear silver(I) N-heterocyclic carbene complex, an anti-inflammatory and apoptosis mediator

Iqbal MA, Umar MI, Haque RA, Khadeer Ahamed MB, Asmawi MZ, Majid AM

J Inorg Biochem, 2015 May;146:1-13.
PMID: 25699476 DOI: 10.1016/j.jinorgbio.2015.02.001

Chronic inflammation intensifies the risk for malignant neoplasm, indicating that curbing inflammation could be a valid strategy to prevent or cure cancer. Cancer and inflammation are inter-related diseases and many anti-inflammatory agents are also used in chemotherapy. Earlier, we have reported a series of novel ligands and respective binuclear Ag(I)-NHC complexes (NHC=N-heterocyclic carbene) with potential anticancer activity. In the present study, a newly synthesized salt (II) and respective Ag(I)-NHC complex (III) of comparable molecular framework were prepared for a further detailed study. Preliminarily, II and III were screened against HCT-116 and PC-3 cells, wherein III showed better results than II. Both the compounds showed negligible toxicity against normal CCD-18Co cells. In FAM-FLICA caspase assay, III remarkably induced caspase-3/7 in HCT-116 cells most probably by tumor necrosis factor-alpha (TNF-α) independent intrinsic pathway and significantly inhibited in vitro synthesis of cytokines, interleukin-1 (IL-1) and TNF-α in human macrophages (U937 cells). In a cell-free system, both the compounds inhibited cyclooxygenase (COX) activities, with III being more selective towards COX-2. The results revealed that III has strong antiproliferative property selectively against colorectal tumor cells which could be attributed to its pro-apoptotic and anti-inflammatory abilities.
Safety assessment of widely used fermented virgin coconut oil (Cocos nucifera) in Malaysia: Chronic toxicity studies and SAR analysis of the active components

Ibrahim AH, Khan MS, Al-Rawi SS, Ahamed MB, Majid AS, Al-Suede FS, et al.

Regul Toxicol Pharmacol, 2016 Nov;81:457-467.
PMID: 27756558 DOI: 10.1016/j.yrtph.2016.10.004

Fermented Virgin Coconut Oil (FVCO) is widely used in the Southeast Asia as food and traditional medicine. The objective of the present study is the evaluation of chronic safety of the commercialized FVCO of Malaysia and other Southeast Asian countries. A single dose of 5000 mg/kg of FVCO was administered orally in rats (each group, n = 5) for the acute toxicity study and 175, 550 and 2000 mg/kg for sub-chronic and chronic studies (each group, n = 10), respectively. The behavior, mortality, and body weight of the rats were assessed to determine the toxic effects of FVCO. The haematology, biochemistry and histopathology of the treated rats were evaluated. The treated rats were safe with the dose of 5000 mg/kg in acute, sub-chronic and chronic indication. Abnormal clinical signs and morphology (gross necroscopy), changes of organ weight, anomalous haematology and biochemistry indexes were not found in comparison with the control (p > 0.05). In general, food and water intake were higher in the treated rats related to control. It was concluded that the presence of the antioxidant active compounds of FVCO might be the reason of safety. The structure activity relationship (SAR) provides a comprehensive mechanism to determine the safety that is the presence of the electron donating phenolic groups, carbonyl groups, and carboxylic acid in the ortho and meta position of the aromatic rings. The SAR showed the antioxidant properties of myristic acid and lauric acid determined by GC-MS analysis. This result suggests the safety of FVCO for chronic use, nutritional activity that FVCO formulation complies the requirements of regulatory agencies.
Mononuclear dioxomolybdenum(VI) thiosemicarbazonato complexes: Synthesis, characterization, structural illustration, in vitro DNA binding, cleavage, and antitumor properties

Hussein MA, Guan TS, Haque RA, Khadeer Ahamed MB, Abdul Majid AM

Spectrochim Acta A Mol Biomol Spectrosc, 2015 Feb 05;136 Pt C:1335-48.
PMID: 25456676 DOI: 10.1016/j.saa.2014.10.021

Four dioxomolybdenum(VI) complexes were synthesized by reacting [MoO2(acac)2] with N-ethyl-2-(5-bromo-2-hydroxybenzylidene) hydrazinecarbothioamide (1), N-ethyl-2-(5-allyl-3-methoxy-2-hydroxybenzylidene) hydrazinecarbothioamide (2), N-methyl-2-(3-tert-butyl-2-hydroxybenzylidene) hydrazinecarbothioamide (3), and N-ethyl-2-(3-methyl-2-hydroxybenzylidene) hydrazinecarbothioamide (4). The molecular structures of 1, 2, and all the synthesized complexes were determined using single crystal X-ray crystallography. The binding properties of the ligand and complexes with calf thymus DNA (CT-DNA) were investigated via UV, fluorescence titrations, and viscosity measurement. Gel electrophoresis revealed that all the complexes cleave pBR 322 plasmid DNA. The cytotoxicity of the complexes were studied against the HCT 116 human colorectal cell line. All the complexes exhibited more pronounced activity than the standard reference drug 5-fluorouracil (IC50 7.3μM). These studies show that dioxomolybdenum(VI) complexes could be potentially useful in chemotherapy.
Diaminobenzene schiff base, a novel class of DNA minor groove binder

Helal MH, Al-Mudaris ZA, Al-Douh MH, Osman H, Wahab HA, Alnajjar BO, et al.

Int J Oncol, 2012 Aug;41(2):504-10.
PMID: 22614449 DOI: 10.3892/ijo.2012.1491

Molecules that target the deoxyribonucleic acid (DNA) minor groove are relatively sequence specific and they can be excellent carrier structures for cytotoxic chemotherapeutic compounds which can help to minimize side effects. Two novel isomeric derivatives of diaminobenzene Schiff base [N,N'-bis (2-hydroxy-3-methoxybenzylidene)-1,2-diaminobenzene (2MJ) and N,N'-bis(2-hydroxy-3-methoxybenzylidene)-1,3-diaminobenzene (2MH)] were analyzed for their DNA minor groove binding (MGB) ability using viscometry, UV and fluorescence spectroscopy, computational modeling and clonogenic assay. The result shows that 2MJ and 2MH are strong DNA MGBs with the latter being more potent. 2MH can form interstrand hydrogen bond linkages at its oxygens with N3 of adenines. Changing the 2-hydroxy-3-methoxybenzylidene binding position to the 1,3 location on the diaminobenzene structure (2MJ) completely removed any viable hydrogen bond formation with the DNA and caused significant decrease in binding strength and minor groove binding potency. Neither compound showed any significant cytotoxicity towards human breast, colon or liver cancer cell lines.
Fulltext Correlation of antiangiogenic, antioxidant and cytotoxic activities of some Sudanese medicinal plants with phenolic and flavonoid contents

Hassan LE, Ahamed MB, Majid AS, Baharetha HM, Muslim NS, Nassar ZD, et al.

BMC Complement Altern Med, 2014 Oct 20;14:406.
PMID: 25331269 DOI: 10.1186/1472-6882-14-406

BACKGROUND: Consumption of medicinal plants to overcome diseases is traditionally belongs to the characteristics of most cultures on this earth. Sudan has been a host and cradle to various ancient civilizations and developed a vast knowledge on traditional medicinal plants. The present study was undertaken to evaluate the antioxidant, antiangiogenic and cytotoxic activities of six Sudanese medicinal plants which have been traditionally used to treat neoplasia. Further the biological activities were correlated with phytochemical contents of the plant extracts.
METHODS: Different parts of the plants were subjected to sequential extraction method. Cytotoxicity of the extracts was determined by dimethylthiazol-2-yl)- 2,5diphenyl tetrazolium bromide (MTT) assay on 2 human cancer (colon and breast) and normal (endothelial and colon fibroblast) cells. Anti-angiogenic potential was tested using ex vivo rat aortic ring assay. DPPH (1,1-diphenyl-2-picrylhydrazyl) assay was conducted to screen the antioxidant capabilities of the extracts. Finally, total phenolic and flavonoid contents were estimated in the extracts using colorimetric assays.
RESULTS: The results indicated that out of 6 plants tested, 4 plants (Nicotiana glauca, Tephrosia apollinea, Combretum hartmannianum and Tamarix nilotica) exhibited remarkable anti-angiogenic activity by inhibiting the sprouting of microvessels more than 60%. However, the most potent antiangiogenic effect was recorded by ethanol extract of T. apollinea (94.62%). In addition, the plants exhibited significant antiproliferative effects against human breast (MCF-7) and colon (HCT 116) cancer cells while being non-cytotoxic to the tested normal cells. The IC50 values determined for C. hartmannianum, N. gluaca and T. apollinea against MCF-7 cells were 8.48, 10.78 and 29.36 μg/ml, respectively. Whereas, the IC50 values estimated for N. gluaca, T. apollinea and C. hartmannianum against HCT 116 cells were 5.4, 20.2 and 27.2 μg/ml, respectively. These results were more or less equal to the standard reference drugs, tamoxifen (IC50 = 6.67 μg/ml) and 5-fluorouracil (IC50 = 3.9 μg/ml) tested against MCF-7 and HCT 116, respectively. Extracts of C. hartmannianum bark and N. glauca leaves demonstrated potent antioxidant effect with IC50s range from 9.4-22.4 and 13.4-30 μg/ml, respectively. Extracts of N. glauca leaves and T apollinea aerial parts demonstrated high amount of flavonoids range from 57.6-88.1 and 10.7-78 mg quercetin equivalent/g, respectively.
CONCLUSIONS: These results are in good agreement with the ethnobotanical uses of the plants (N. glauca, T. apollinea, C. hartmannianum and T. nilotica) to cure the oxidative stress and paraneoplastic symptoms caused by the cancer. These findings endorse further investigations on these plants to determine the active principles and their mode of action.
Evaluation of in vitro and in vivo anti-inflammatory effects of (-)-pseudosemiglabrin, a major phytoconstituent isolated from Tephrosia apollinea (Delile) DC

Hassan LE, Dahham SS, Fadul SM, Umar MI, Majid AS, Khaw KY, et al.

J Ethnopharmacol, 2016 Aug 20.
PMID: 27553975 DOI: 10.1016/j.jep.2016.08.023

Tephrosia apollinea (Delile) DC (Leguminosae) has been used in folk medicine in Arabian countries to treat inflammatory disorders. The plant has been described to treat swelling, bone fracture, bronchitis, cough, earache and wounds.
Chemotherapeutic potentials of the stem bark of Balanite aegyptiaca (L.) Delile: an antiangiogenic, antitumor and antioxidant agent

Hassan LE, Dahham SS, Saghir SA, Mohammed AM, Eltayeb NM, Majid AM, et al.

BMC Complement Altern Med, 2016 Oct 19;16(1):396.
PMID: 27760539

Balanite aegyptiaca (L.) Delile, is a plant with extensive medicinal properties. Its stem bark is traditionally known for its spasmolytic and antiepileptic properties and used to treat yellow fever, jaundice and syphilis. Angiogenesis (sprouting of new blood vessels) is crucial for tumor growth and metastasis. The goal of this study is investigate the antiangiogenic, cytotoxicity and antioxidant activity as well as antitumor in vivo properties of B. aegyptiaca stem bark extracts.
Fulltext High-performance Thin-layer Chromatography Method Development, Validation, and Simultaneous Quantification of Four Compounds Identified in Standardized Extracts of Orthosiphon stamineus

Hashim S, Beh HK, Hamil MS, Ismail Z, Majid AM

Pharmacognosy Res, 2016 Oct-Dec;8(4):238-243.
PMID: 27695261

CONTEXT: Orthosiphon stamineus is a medicinal herb widely grown in Southeast Asia and tropical countries. It has been used traditionally as a diuretic, abdominal pain, kidney and bladder inflammation, gout, and hypertension.
AIMS: This study aims to develop and validate the high-performance thin layer chromatography (HPTLC) method for quantification of rosmarinic acid (RA), 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF), sinensitin (SIN) and eupatorin (EUP) found in ethanol, 50% ethanol and water extract of O. stamineus leaves.
MATERIALS AND METHODS: HPTLC method was conducted using an HPTLC system with a developed mobile phase system of toluene: ethyl acetate: formic acid (3:7:0.1) performed on precoated silica gel 60 F254 TLC plates. The method was validated based on linearity, accuracy, precision, limit of detection, limit of quantification (LOQ), and specificity, respectively. The detection of spots was observed at ultraviolet 254 nm and 366 nm.
RESULTS: The linearity of RA, TMF, SIN, and EUP were obtained between 10 and 100 ng/spot with high correlation coefficient value (R2) of more than 0.986. The limit of detection was found to be 122.47 ± 3.95 (RA), 43.38 ± 0.79 (SIN), 17.26 ± 1.16 (TMF), and 46.80 ± 1.33 ng/spot (EUP), respectively. Whereas the LOQ was found to be 376.44 ± 6.70 (RA), 131.45 ± 2.39 (SIN), 52.30 ± 2.01 (TMF), and 141.82 ± 1.58 ng/spot (EUP), respectively.
CONCLUSION: The proposed method showed good linearity, precision, accuracy, and high sensitivity. Hence, it may be applied in a routine quantification of RA, SIN, TMF, and EUP found in ethanol, 50% of ethanol and water extract of O. stamineus leaves.
SUMMARY: HPTLC method provides rapid estimation of the marker compound for routine quality control analysis.The established HPTLC method is rapid for qualitative and quantitative fingerprinting of Orthosiphon stamineus extract used for commercial product.Four identified markers (RA, SIN, EUP and TMF) found in three a different type of O. stamineus extracts specifically ethanol, 50% ethanol and water extract were successfully quantified using HPTLC method. Abbreviations Used: HPTLC: High-performance thin layer chromatography; RA: Rosmarinic acid; TMF: 3'-hydroxy-5,6,7,4'-tetramethoxyflavone; SIN: Sinensitin; EUP: Eupatorin; E: Ethanol; EW: 50% ethanol; W: Water; BK: Batu Kurau; KB: Kepala Batas; S: Sik; CJ: Changkat Jering; SB: Sungai Buloh.
KEYWORDS: rosmarinic acid; Eupatorin; Orthosiphon stamineus; high-performance thin-layer chromatography; sinensitin; validation
Sterically tuned Ag(I)- and Pd(II)-N-heterocyclic carbene complexes of imidazol-2-ylidenes: synthesis, crystal structures, and in vitro antibacterial and anticancer studies

Haque RA, Salman AW, Budagumpi S, Abdullah AA, Majid AM

Metallomics, 2013 Jun;5(6):760-9.
PMID: 23645390 DOI: 10.1039/c3mt00051f

Unsymmetrically substituted sterically tuned Pd(II)–NHC complexes of the general formula [PdCl2(NHC)2] (NHC = 1-allyl-3-methylimidazolin-2-ylidene, 7; 1-allyl-3-butylimidazol-2-ylidene, 8; 1-benzyl-3-butyl imidazolin-2-ylidene, 9) were prepared through transmetallation from their corresponding Ag(I)–NHC complexes. The Pd complexes were structurally characterized by different spectroscopic and X-ray diffraction methods. Complexes 7 and 9 adopted a trans–anti arrangement of the NHC ligands, whereas complex 8 adopted a cis–syn arrangement. Preliminary antibiogram studies using Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria showed that Ag(I)–NHC complexes demonstrate higher activity compared with Pd(I)–NHC complexes. Furthermore, Pd(II)–NHC complexes were evaluated for their anticancer potential using the human colorectal cancer cell line. A higher anticancer activity was observed for complexes 8 and 9, with 26.5 and 6.6 mM IC50 values, respectively.
Phytochemical analysis, cytotoxic activity and constituents-activity relationships of the leaves of Cinnamomum iners (Reinw. ex Blume-Lauraceae)

Ghalib RM, Hashim R, Sulaiman O, Mehdi SH, Anis Z, Rahman SZ, et al.

Nat Prod Res, 2012;26(22):2155-8.
PMID: 22181707 DOI: 10.1080/14786419.2011.633083

The leaves of Cinnamomum iners (Reinw. ex Blume-Lauraceae) have been refluxed successively with chloroform and alcohol to get chloroform extract and alcoholic extract. Both the extracts have been assayed for cytotoxicity against human colorectal tumour cells. The chloroform extract exhibited significant cytotoxicity with IC(50) 31 µg mL(-1) (p 200 µg mL(-1). The chloroform extract has been further proceeded for chemical analysis by GC-TOFMS and 178 components were identified including acids, amines, amides, aldehydes, alcohols, esters, benzene derivatives, bicyclic compounds, terpenes, hydrocarbons, naphthalene derivatives, furan derivatives, azulenes, etc. Nine components representing 51.73% of the total chloroform extract were detected as major components. Caryophyllene (14.41%) and Eicosanoic acid ethyl ester (12.17%) are the most prominent components of the chloroform extract. β-Caryophyllene (14.41%) as most abundant compound supports potent cytotoxicity as shown by chloroform extract.
A novel caryophyllene type sesquiterpene lactone from Asparagus falcatus (Linn.); structure elucidation and anti-angiogenic activity on HUVECs

Ghalib RM, Hashim R, Sulaiman O, Mehdi SH, Valkonen A, Rissanen K, et al.

Eur J Med Chem, 2012 Jan;47(1):601-7.
PMID: 22074984 DOI: 10.1016/j.ejmech.2011.10.037

In this study the novel caryophyllene type sesquiterpene lactone (aspfalcolide) has been isolated from the leaves of Asparagus falcatus (Linn.) and characterized by IR, 1D NMR, 2D NMR, EI-MS, HR-ESI-MS and X-ray single crystal diffraction analysis. The aspfalcolide crystallizes in the orthorhombic space group P2(1)2(1)2(1) with a = 6.37360(10), b = 7.6890(2), c = 27.3281(6) Å, α = β = γ = 90(°) and Z = 4. One intermolecular O-H⋯O hydrogen bond enforces these natural molecules to form infinite chains through the crystal. Aspfalcolide was screened for its anti-angiogenic activity in human umbilical vein endothelial cells (HUVECs) and the result showed the remarkable inhibitory effect of aspfalcolide on the proliferation (IC(50) 1.82 μM), migration and tube formation of HUVECs.
Mutagenicity and preclinical safety assessment of the aqueous extract of Clinacanthus nutans leaves

Farsi E, Esmailli K, Shafaei A, Moradi Khaniabadi P, Al Hindi B, Khadeer Ahamed MB, et al.

Drug Chem Toxicol, 2016 Oct;39(4):461-73.
PMID: 27033971 DOI: 10.3109/01480545.2016.1157810

CONTEXT: Clinacanthus nutans (CN) is used traditionally for treating various illnesses. Robust safety data to support its use is lacking.
OBJECTIVE: To evaluate the adverse effects of aqueous extract of CN leaves (AECNL).
MATERIALS AND METHODS: The oral toxicity of the AECNL was tested following Organisation for Economic Co-operation and Development (OECD) guidelines. Mutagenicity (Ames test) of AECNL was evaluated using TA98 and TA100 Salmonella typhimurium strains.
RESULTS: No mortality or morbidity was found in the animals upon single and repeated dose administration. However, significant body weight loss was observed at 2000 mg/kg during sub-chronic (90 d) exposure. In addition, increased eosinophil at 500 mg/kg and decreased serum alkaline phosphatase levels at 2000 mg/kg were observed in male rats. Variations in glucose and lipid profiles in treated groups were also observed compared to control. Ames test revealed no evidence of mutagenic or carcinogenic effects at 500 μg/well of AECNL.
CONCLUSION: The median lethal dose (LD50) of the AECNL is >5000 mg/kg and the no-observed-adverse-effect level is identified to be greater than 2000 mg/kg/day in 90-d study.
Fulltext The Anticancer, Antioxidant and Antimicrobial Properties of the Sesquiterpene β-Caryophyllene from the Essential Oil of Aquilaria crassna

Dahham SS, Tabana YM, Iqbal MA, Ahamed MB, Ezzat MO, Majid AS, et al.

Molecules, 2015;20(7):11808-29.
PMID: 26132906 DOI: 10.3390/molecules200711808

The present study reports a bioassay-guided isolation of β-caryophyllene from the essential oil of Aquilaria crassna. The structure of β-caryophyllene was confirmed using FT-IR, NMR and MS. The antimicrobial effect of β-caryophyllene was examined using human pathogenic bacterial and fungal strains. Its anti-oxidant properties were evaluated by DPPH and FRAP scavenging assays. The cytotoxicity of β-caryophyllene was tested against seven human cancer cell lines. The corresponding selectivity index was determined by testing its cytotoxicity on normal cells. The effects of β-caryophyllene were studied on a series of in vitro antitumor-promoting assays using colon cancer cells. Results showed that β-caryophyllene demonstrated selective antibacterial activity against S. aureus (MIC 3 ± 1.0 µM) and more pronounced anti-fungal activity than kanamycin. β-Caryophyllene also displayed strong antioxidant effects. Additionally, β-caryophyllene exhibited selective anti-proliferative effects against colorectal cancer cells (IC50 19 µM). The results also showed that β-caryophyllene induces apoptosis via nuclear condensation and fragmentation pathways including disruption of mitochondrial membrane potential. Further, β-caryophyllene demonstrated potent inhibition against clonogenicity, migration, invasion and spheroid formation in colon cancer cells. These results prompt us to state that β-caryophyllene is the active principle responsible for the selective anticancer and antimicrobial activities of A. crassnia. β-Caryophyllene has great potential to be further developed as a promising chemotherapeutic agent against colorectal malignancies.
Fulltext In vivo toxicity and antitumor activity of essential oils extract from agarwood (Aquilaria crassna)

Dahham SS, Hassan LE, Ahamed MB, Majid AS, Majid AM, Zulkepli NN

BMC Complement Altern Med, 2016 Jul 22;16:236.
PMID: 27450078 DOI: 10.1186/s12906-016-1210-1

Aquilaria crassna has been used in traditional Asian medicine to treat vomiting, rheumatism, asthma, and cough. Furthermore, earlier studies from our laboratory have revealed that the essential oil extract from agarwood inhibited colorectal carcinoma cells. Despite of the wide range of ethno-pharmacological uses of agarwood, its toxicity has not been previously evaluated through systematic toxicological studies. Therefore, the potential safety of essential oil extract and its in vivo anti-tumor activity had been investigated.

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