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Department of Bioactive Products
Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology
Phytochemistry (isolation and structural elucidation of natural compounds), semisynthesis of natural compounds, pharmaceutical and medicinal chemistry
Nguyen Trong Dan, Hoang Duc Quang, Vuong Van Truong, Do Huu Nghi, Nguyen Manh Cuong, To Dao Cuong, Tran Quoc Toan, Long Giang Bach, Nguyen Huu Thuan Anh, Nguyen Thi Mai, Ngo Thi Lan, Luu Van Chinh, and Pham Minh Quan
Scientific Reports, eISSN: 20452322, Published: 1 December 2020 Springer Science and Business Media LLC
The addition of chalcone and amine components into indirubin-3′-oxime resulted in 15 new derivatives with high yields. Structures of new derivatives were also elucidated through 1D, 2D-NMR and HR-MS(ESI) spectra and X-ray crystallography. All designed compounds were screened for cytotoxic activity against four human cancer cell lines (HepG2, LU-1, SW480 and HL-60) and one human normal kidney cell line (HEK-293). Compound 6f exhibited the most marked cytotoxicity meanwhile cytotoxicity of compounds 6e , 6h and 6l was more profound toward cancer cell lines than toward normal cell. These new derivatives were further analyzed via molecular docking studies on GSK-3β enzyme. Docking analysis shows that most of the derivatives exhibited potential inhibition activity against GSK-3β with characteristic interacting residues in the binding site. The fast pulling of ligand scheme was then employed to refine the binding affinity and mechanism between ligands and GSK-3β enzyme. The computational results are expected to contribute to predicting enzyme target of the trial inhibitors and their possible interaction, from which the design of new cytotoxic agents could be created in the future.
Nguyen Manh Cuong, Ninh The Son, Ngu Truong Nhan, Pham Ngoc Khanh, Tran Thu Huong, Nguyen Thi Thu Tram, Giampietro Sgaragli, Amer Ahmed, Alfonso Trezza, Ottavia Spiga, and Fabio Fusi
Planta Medica, ISSN: 00320943, eISSN: 14390221, Pages: 284-293, Published: 1 March 2020 Georg Thieme Verlag KG
Abstract Dalbergia species heartwood, widely used in traditional medicine to treat various cardiovascular diseases, might represent a rich source of vasoactive agents. In Vietnam, Dalbergia tonkinensis is an endemic tree. Therefore, the aim of the present work was to investigate the vascular activity of R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol isolated from the heartwood of D. tonkinensis and to provide circular dichroism features of its R absolute configuration. The vascular effects of R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol were assessed on the in vitro mechanical activity of rat aorta rings, under isometric conditions, and on whole-cell Ba2+ currents through CaV1.2 channels (IBa1.2) recorded in single, rat tail main artery myocytes by means of the patch-clamp technique. R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol showed concentration-dependent, vasorelaxant activity on both endothelium-deprived and endothelium intact rings precontracted with the α 1 receptor agonist phenylephrine. Neither the NO (nitric oxide) synthase inhibitor Nω-nitro-L-arginine methyl ester nor the cyclooxygenase inhibitor indomethacin affected its spasmolytic activity. R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol-induced vasorelaxation was antagonized by (S)-(−)-Bay K 8644 and unaffected by tetraethylammonium plus glibenclamide. In patch-clamp experiments, R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol inhibited IBa1.2 in a concentration-dependent manner and significantly decreased the time constant of current inactivation. R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol likely stabilized the channel in its closed state, as suggested by molecular modelling and docking simulation to the CaV1.2 channel α 1c subunit. In conclusion, D. tonkinensis species may represent a source of agents potentially useful for the development of novel antihypertensive drugs.
Ninh The Son, Midori Suenaga, Yoiichi Matsunaga, Luu Van Chinh, Miwa Kubo, Kenichi Harada, Nguyen Manh Cuong, and Yoshiyasu Fukuyama
Journal of Natural Medicines, ISSN: 13403443, eISSN: 18610293, Pages: 257-263, Published: 1 January 2020 Springer Science and Business Media LLC
The vulnerable plant Dalbergia tonkinensis Prain is a rare species in Vietnam. In the course of our studies on biologically active plants, we performed serine protease enzyme screenings. The results suggest that at concentrations of 25–250 ng/mL, methanol extracts of leaf and root, root ethanol extract and its dichloromethane fraction, and heartwood water decoction extract can serve as useful sources to stimulate trypsin enzyme activity. In addition, water decoction extracts of leaf and stem bark may explain unknown ethno-pharmacology due to the high inhibitory effects in enzyme assays using trypsin, chymotrypsin, and elastase. Among 23 isolated compounds and two semi-synthetic derivatives tested, quercetin (17) inhibits the activities of trypsin and chymotrypsin with IC50 9.7 µM. Flavonoids categorized as flavanone, isoflavanone, flavone, isoflavone, pretocarpan, aurone, and neoflavanone demonstrated variable activities. Several substitutions are closely correlated with protease actions, including hydroxylation at C-3 and C-3′ in flavone and C-5 and C-3′ in isoflavone, hydroxylation at C-3, C-5 and C-3′, carboxylation at C-6 and C-8, and 7-substitution in flavanone; 7-substitution and methoxylation at C-3′ in isoflavanone; and lactone ring opening in neoflavanone. In the assessment of casein cleavage, at a dose of 25 ng/mL, leaf water decoction extract demonstrates an inhibitory effect on casein cleavage by trypsin, whereas ethanol and methanol extracts of the root caused activation.
Le Xuan Duy, Vinh Le Ba, Dan Gao, Vu Dinh Hoang, Tran Quoc Toan, Seo Young Yang, Dao Duy Quang, Young Ho Kim, and Nguyen Manh Cuong
Natural Product Research, ISSN: 14786419, eISSN: 14786427, Published: 2020 Informa UK Limited
Nine bioactive compounds, including one new dihydroisocoumarin glycoside, 3S-thunberginol C 6-O-β-D-glucopyranoside (1a/1b), were isolated by chromatographic separation from the fruits of the Vietnamese medicinal plant Docynia indica (Wall.) Decne. 3S-thunberginol C 6-O-β-D-glucopyranoside was determined as a mixture of boat-like conformers based on NMR evidence and density functional theory (DFT) calculations. The in vitro inhibition of soluble epoxide hydrolase (sEH) by the isolated compounds was comparable to that of AUDA (positive control), yielding IC50 values ranging from 10.0 ± 0.6 to 88.4 ± 0.2 µM. Among isolated compounds, 3-methoxy-4-hydroxy-benzoic acid (7) and 2',6'-dihydroxy 3',4'-dimethoxychalcone (9) were identified as a potent inhibitor of sEH, with IC50 values of 19.3 ± 2.2 and 10.0 ± 0.6 mM, respectively. These results suggest that the fruits of D. indica may be useful as daily supplements for the prevention of cardiovascular and other sEH-related diseases.[Formula: see text].
Ninh The Son, Yoshiyasu Fukuyama, and Nguyen Manh Cuong
Chemistry of Natural Compounds, ISSN: 00093130, eISSN: 15738388, Pages: 854-856, Published: 1 September 2019 Springer Science and Business Media LLC
A new sesquiterpene, rel-(3R,6S,7S)-6α-hydroxycyclonerolidol (1), along with three known compounds, including neroplomacrol (2), naringin (3), and p-formylphenol (4), was isolated from the heartwood of Dalbergia tonkinensis. Their chemical structures were elucidated based on spectroscopic analysis.
Ninh The Son, Mari Kamiji, Tran Thu Huong, Miwa Kubo, Nguyen Manh Cuong, and Yoshiyasu Fukuyama
Medicinal Chemistry Research, ISSN: 10542523, eISSN: 15548120, Pages: 1441-1447, Published: 1 September 2019 Springer Science and Business Media LLC
Phytochemical investigations of the leaves and roots of Dalbergia tonkinensis led to the isolation of a new isoflavone glycoside derivative, isocaviunin 7-O-β-D-apiofuranosyl-(1 → 6)-β-D-glucopyranoside (1), and a new scalemic sesquiterpene lactone, 3,7-dimethyl-3-vinylhexahydro-6,7-bifuran-3(2H)-one (2), along with the previously known compounds 3-16, and nine other known compounds 17-25 were isolated from the leaves of Cratoxylum formosum. The chemical structures of the isolated compounds were elucidated by 1D- and 2D-NMR analyses as well as MS spectroscopic data. The results suggest that flavonoids are characteristic of both plants. In the DPPH radical scavenging assay, (3 R)-vestitol (5) and isoquercetin (24) possessed the strongest antioxidative IC50 values of 42.20 µg/mL and 45.63 µg/mL, respectively, and their values were comparable to that of the positive control catechin (IC50 42.98 µg/mL).
To Dao Cuong, Hoang Thi Ngoc Anh, Tran Thu Huong, Pham Ngoc Khanh, Vu Thi Ha, Tran Manh Hung, Young Ho Kim, and Nguyen Manh Cuong
Natural Product Sciences, ISSN: 12263907, eISSN: 22889027, Pages: 348-353, Published: 2019 The Korean Society of Pharmacognosy (KAMJE)
− Soluble epoxide hydrolases (sEH) are enzymes present in all living organisms, metabolize epoxy fatty acids to 1,2-diols. sEH in the metabolism of polyunsaturated fatty acids plays a key role in inflammation. In addition, the endogenous lipid mediators in cardiovascular disease are also broken down to diols by the action of sEH that enhanced cardiovascular protection. In this study, sEH inhibitory guided fractionation led to the isolation of five phenolic compounds trans-resveratrol (1), trans-piceatannol (2), sulfuretin (3), (+)-balanophonin (4), and cassigarol E (5) from the ethanol extract of the seeds of Passiflora edulis Sims cultivated in Vietnam. The chemical structures of isolated compounds were determined by the interpretation of NMR spectral data, mass spectra, and comparison with data from the literature. The soluble epoxide hydrolase (sEH) inhibitory activity of isolated compounds was evaluated. Among them, trans-piceatannol (2) showed the most potent inhibitory activity on sEH with an IC50 value of 3.4 μM. This study marks the first time that sulfuretin (3) was isolated from Passiflora edulis as well as (+)-balanophonin (4), and cassigarol E (5) were isolated from Passiflora genus.
Tran Thu Huong, Vu Thi Ha, To Dao Cuong, Ninh The Son, Tran Quoc Toan, Hoang Thi Ngoc Anh, Nguyen Thi Thu Tram, Sun Hee Woo, Young Ho Kim, and Nguyen Manh Cuong
Natural Product Communications, ISSN: 1934578X, eISSN: 15559475, Pages: 1-5, Published: 2019 SAGE Publications
Paramignya trimera (Oliv.) Guill. (Rutaceae), mostly distributed in the southern regions of Vietnam, has been used as a medicinal plant for treatment of liver diseases and cancer. From the methanol extract of the roots and stems of P. trimera, 3 new compounds (1-3) were isolated, including ninhvanin B (1), paramitrimerol (2), and parabacunoic acid (3), and a known alkaloid, citrusinine-I (4). The structures of these compounds were elucidated by electrospray ionization mass spectrometry and nuclear magnetic resonance spectral analysis, as well as by comparison with literature data.
Pham Ngoc Khanh, Tran Thu Huong, Ottavia Spiga, Alfonso Trezza, Ninh The Son, To Dao Cuong, Vu Thi Ha, and Nguyen Manh Cuong
Revista Internacional de Andrologia, ISSN: 1698031X, eISSN: 16980409, Pages: 147-158, Published: October - December 2018 Elsevier BV
OBJECTIVE Prismatomeris memecyloides Craib (Rubiaceae) is a medicinal plant traditionally used by ethnic minorities in Vietnam for the treatment of erectile dysfunction (ED). The aim of this study was to investigate the chemical compositions and screen in silico its possible inhibitory effect against PDE-5 which reduced cyclic guanosine-3',5'-monophosphate (cGMP) levels and indirectly caused the male ED. METHODS Separation of natural compounds were carried out on chromatographic column with silica gel or reversed phase materials, eluting with different solvent gradients. The structures of all isolated compounds were elucidated on the basis of spectroscopic data (HR-MS, 1D/2D-NMR). Docking simulation study of compound (1-7) was performed by using flexible side chains protocol based on Iterated Local Search Global Optimizer Algorithm of AutoDock/Vina v.1.1.2. Pharmacokinetic parameters and toxicity prediction were also calculated by appropriate softwares. RESULTS From the methanol extract of roots of P. memecyloides collected in Vietnam, seven compounds including four anthraquinone/one anthraquinone glycoside namely damnacanthal (1), lucidin-ω-methyl ether (2), 3-methylalizarin (3), rubiadin-3-methyl ether (4), and 1-O-methylrubiadin 3-O-primeveroside (5) along with two iridoid glucosides, asperulosidic acid (6) and aitchisonide A (7) were isolated. The molecular modeling results showed that 5 anthraquinone compounds possess the lowest binding energies to PDE-5. The anthraquinone glucoside 1-O-methylrubiadin 3-O-primeveroside (5) potentially inhibited PDE-5 similarly to commercial PDE-5Is sildenafil (SLD) and tadalafil (TLD). Calculated pharmacokinetic results like pIC50,pred; miLogP, TPSA, enzyme inhibitory of anthraquinone glucoside (5) were similar and even higher to those of the commercial PDE-5 inhibitors. Especially the predictive toxicity of 1-O-methylrubiadin 3-O-primeveroside (5) was even lower than those of SLD and TLD. CONCLUSION This is the first study to find a scientific-based evidence for the ethnic use of P. memecyloides as medicinal plant for the treatment of ED. The result indicates that the anthraquinones (damnacanthal (1), lucidin-ω-methyl ether (2), 3-methylalizarin (3) and rubiadin-3-methyl ether (4)), especially anthraquinone glycoside (1-O-methylrubiadin 3-O-primeveroside (5)) are compounds of potential novel drug class for the ED treatment.
Ninh The Son, Masataka Oda, Naoki Hayashi, Daiki Yamaguchi, Yu Kawagishi, Fumi Takahashi, Kenichi Harada, Nguyen Manh Cuong, and Yoshiyasu Fukuyama
Natural Product Communications, ISSN: 1934578X, eISSN: 15559475, Pages: 157-161, Published: February 2018 SAGE Publications
The vulnerable plant Dalbergia tonkinensis Prain, is a rare species, native to Vietnam. Phytochemical investigations and biological evaluations of this species are quite limited. Antimicrobial screening has suggested that, at the low dose of 1.0 mg/mL, the methanol extracts of the leaf, stem bark, and root, as well as chloroform fraction of heartwood can serve as useful sources against seven gram-positive skin microbacteria, Bacillus cereus (ATCC27522), Escherichia coli (JM109), Staphylococcus aureus (ATCC25923), Staphylococcus epidermidis (ATCC14990), Streptococcus pneumonia (ATCC49619), Streptococcus pyogenes (ATCC12344), and Vibrio parahaemolyticus (RIMD2210010), and four oral gram-positive microbacteria Streptococcus mutans (ATCC 25175), Streptococcus mitis (ATCC903), Streptococcus sobrinus (ATCC 33478), and Porphyromonas gingivalis (ATCC33277), with an inhibitory percentage of 60-80% growth for several strains Bacillus cereus, Escherichia coli, and Streptococcus pneumonia. We further assessed antimicrobial activities of the enriched diverse flavonoids from chloroform fraction of its heartwood. Extensive structural activity relationship studies showed structure function closely related to the antimicrobial activity, in which methoxylation at C-2’, and 4’ in isoflavanones, hydroxylation at C-3’ in flavones, substitution at C-5 in isoflavones, and lactone opened ring in neoflavonoids were found to increase the effective inhibitions. In the second antimicrobial assessment, the isolated flavonoid liquiritigenin showed the MIC values of 50, and 100 μg/mL against the microbacterial strains Staphylococcus aureus subsp. aureus (ATCC 11632), and Aspergillus niger (439), respectively, whereas the MIC value of 100 μg/mL was assignable to biochanin A against microbacterium Staphylococcus aureus subsp. aureus.
Van Nguyen, San-Lang Wang, Ngu Nhan, Thi Nguyen, Nguyen Nguyen, Do Nghi, and Nguyen Cuong
Molecules, eISSN: 14203049, Published: 2018 MDPI AG
Alpha-glucosidase inhibitory activity has been commonly used for the evaluation of antidiabetic property in vitro. The aim of this study is to investigate and characterize Dalbergia tonkinensis as a potential source of antidiabetic compounds. The screening of the active parts used, such as trunk bark, heartwood, and the leaves of Dalbergia tonkinensis indicated that all these extracted parts used with methanol demonstrated potent α-glucosidase inhibitory activity. The in vitro antidiabetic property of Dalbergia tonkinensis was notably recorded for the first time and showed activity (EC50 = 0.17–0.78 mg/mL) comparable to those of reported potent herbal extracts (EC50 = 0.25–4.0 mg/mL) and higher activity than that of acarbose, a commercial antidiabetic drug (EC50 = 1.21 mg/mL). The stability tests revealed that the heartwood of Dalbergia tonkinensis extract (HDT) possesses high pH stability with relative activity in the range of 80–98%. Further bioassay-guided purification led to the isolation of 2 active compounds identified as sativanone and formononetin from the ethyl acetate fraction and water fraction of HDT, respectively. These α-glucosidase inhibitors (aGIs) show promising inhibition against various types of α-glucosidases. Remarkably, these inhibitors were determined as new mammalian aGIs, showing good effect on rat α-glucosidase. The results suggest that Dalbergia tonkinensis is a potent source of aGIs and suggest promise in being developed as functional food with antidiabetic efficacy. The results of this study also enrich our knowledge concerning current biological activity and constituents of Dalbergia tonkinensis species.
Nguyen Manh Cuong, Ngu Truong Nhan, Ninh The Son, Do Huu Nghi, and To Dao Cuong
Bulletin of the Korean Chemical Society, ISSN: 02532964, eISSN: 12295949, Pages: 1511-1514, Published: December 2017 Wiley
Ninh The Son, Kenichi Harada, Nguyen Manh Cuong, and Yoshiyasu Fukuyama
Natural Product Communications, ISSN: 1934578X, eISSN: 15559475, Pages: 1721-1723, Published: November 2017 SAGE Publications
Two new carboxyethylflavanone derivatives, (2 S)-8-carboxyethylnarigenin (2) and (2 S)-6,8-dicarboxyethylpinocembrin (3) were isolated from the heartwood of Dalbergia tonkinensis Prain, along with four known compounds 1, and 4-6. The chemical structures of two new compounds 2 and 3 were elucidated based on analyses of the spectroscopic data, including 1D and 2D NMR, HR-ESI-MS, IR, UV, and CD spectroscopies. By carrying out antimicrobial assay, CH3OH and CHCl3 fractions exhibited weak MIC value at 200 μg/mL against filamentous fungus A. niger (439), whereas the known flavanone 1 and the new carboxyethylflavanone 2 had MIC at 100 μg/mL.
Luu Van Chinh, Le Duc Anh, Nguyen Thi Nga, Nguyen Thi Ha Ly, Vu Thi Ha, Tran Quoc Toan, Nguyen Manh Cuong, and Tran Khac Vu
Letters in Organic Chemistry, ISSN: 15701786, Pages: 603-611, Published: 1 October 2017 Bentham Science Publishers Ltd.
Nguyen Cong Thuy Tram, Ninh The Son, Nguyen Thi Nga, Vu Thi Thu Phuong, Nguyen Thi Cuc, Do Thi Phuong, Gilles Truan, Nguyen Manh Cuong, and Do Thi Thao
Medicinal Chemistry Research, ISSN: 10542523, eISSN: 15548120, Pages: 2057-2064, Published: 1 September 2017 Springer Science and Business Media LLC
A new derivative kaempferol glycoside, kaempferol-3-O-(2-α-l-rhamnopyranosyl)-β-d-glucuronopyranosyl methyl ester (3), together with six other known kaempferol glycosides, kaempferol-3-O-[α-l-rhamnopyranosyl (1→2)]-β-d-galactopyranoside (1), kaempferol-3-O-(2-α-l-rhamnopyranosyl)-β-d-glucuronopyranoside (2), rutin (4), isoquercitrin (5), quercitrin (6), and myricitrin (7) were isolated from the leaves of Phyllanthus acidus (L.) Skeels (Phyllanthaceae). Here, is the first report described the isolation of compound (1) and (2) from the genus Phyllanthus. Compound (1) presents antioxidant activity in 2,2-diphenyl-1-picryl-hydrazyl-hydrate assay. Compound (2) and (3) performed no antioxidant activity in 2,2-diphenyl-1-picryl-hydrazyl-hydrate and thiobarbituric acid reactive substances assays (IC50 > 100 µM). However, compound (2) showed anti-inflammation activity through inhibiting interleukin 6 and tumor necrosis factor alpha production (P < 0.05). Compound (3) also exhibited cytokine modulating activities such as inhibiting tumor necrosis factor alpha, activating interleukin 10 at concentration of 10 µM (P < 0.05). The interleukin 6 cytokine level was also up or down-regulated by compound (3) at two time points; 24 and 48 h. This activeness of compound (3) might induce hepatoprotection in the acute-phase response by activating the signal transducer and activator of transcription 3(STAT3) through cytokine modulation. Together with other kaempferol glycosides, this new derivative compound may mediate the liver-protective activity of the Vietnamese medicinal plant Phyllanthus acidus.
Hong-Jie Zhang, Emily Rumschlag-Booms, Yi-Fu Guan, Dong-Ying Wang, Kang-Lun Liu, Wan-Fei Li, Van H. Nguyen, Nguyen M. Cuong, Djaja D. Soejarto, Harry H. S. Fong, and Lijun Rong
Journal of Natural Products, ISSN: 01633864, eISSN: 15206025, Pages: 1798-1807, Published: 23 June 2017 American Chemical Society (ACS)
Justicia gendarussa, a medicinal plant collected in Vietnam, was identified as a potent anti-HIV-1 active lead from the evaluation of over 4500 plant extracts. Bioassay-guided separation of the extracts of the stems and roots of this plant led to the isolation of an anti-HIV arylnaphthalene lignan (ANL) glycoside, patentiflorin A (1). Evaluation of the compound against both the M- and T-tropic HIV-1 isolates showed it to possess a significantly higher inhibition effect than the clinically used anti-HIV drug AZT. Patentiflorin A and two congeners were synthesized, de novo, as an efficient strategy for resupply as well as for further structural modification of the anti-HIV ANL glycosides in the search for drug leads. Subsequently, it was determined that the presence of a quinovopyranosyloxy group in the structure is likely essential to retain the high degree of anti-HIV activity of this type of compounds. Patentiflorin A was further investigated against the HIV-1 gene expression of the R/U5 and U5/gag transcripts, and the data showed that the compound acts as a potential inhibitor of HIV-1 reverse transcription. Importantly, the compound displayed potent inhibitory activity against drug-resistant HIV-1 isolates of both the nucleotide analogue (AZT) and non-nucleotide analogue (nevaripine). Thus, the ANL glycosides have the potential to be developed as novel anti-HIV drugs.
Nguyen Manh Cuong, Doan Thi Van, Ninh The Son, To Dao Cuong, Pham Ngoc Khanh, Nguyen Quoc Binh, Tran Thi Viet Thanh, Ji Sun Lee, Ah Reum Jo, and Young Ho Kim
Bulletin of the Korean Chemical Society, eISSN: 12295949, Pages: 112-115, Published: 1 January 2017 Wiley
Jang Hoon Kim, Ju-Yeon Yoon, Sun Jung Kwon, In Sook Cho, Nguyen Manh Cuong, Seung-Kook Choi, Young Ho Kim, and Gug Seoun Choi
Journal of Microbiology and Biotechnology, ISSN: 10177825, eISSN: 17388872, Pages: 2138-2140, Published: December 2016 Korean Society for Microbiology and Biotechnology
The goal of this study was to identify a source of natural plant compounds with inhibitory activity against pepper mild mottle virus (PMMoV). We showed, using a half-leaf assay, that murrayafoline-A (1) and isomahanine (2) isolated from the aerial parts of Glycosmis stenocarpa have inhibitory activity against PMMoV through curative, inactivation, and protection effects. Using a leaf-disk assay, we confirmed that 2 inhibited virus replication in Nicotiana benthamiana. Using electron microscopy, we found that a mixture of the virus with 2 resulted in damage to the rod-shaped virus.
Bojjibabu Chidipi, Min-Jeong Son, Joon-Chul Kim, Jeong Hyun Lee, Tran Quoc Toan, Nguyen Manh Cuong, Byung Ho Lee, and Sun-Hee Woo
European Journal of Pharmacology, ISSN: 00142999, eISSN: 18790712, Volume: 784, Pages: 33-41, Published: 5 August 2016 Elsevier BV
We previously reported that murrayafoline-A (1-methoxy-3-methyl-9H-carbazole, Mu-A) increases the contractility of ventricular myocytes, in part, via enhancing Ca(2+) influx through L-type Ca(2+) channels, and that it increases the Ca(2+) transients by activation of protein kinase C (PKC). In the present study, we further examined the cellular mechanisms for the enhancement of contractility and L-type Ca(2+) current (ICa,L) by Mu-A. Cell shortening and ICa,L were measured in rat ventricular myocytes using a video edge detection method and perforated patch-clamp technique, respectively. We found that the positive inotropic effect of Mu-A was not affected by pre-exposure to the β-adrenoceptor antagonist propranolol, the protein kinase A (PKA) inhibitors KT5720 or H-89, or the phospholipase C inhibitor U73122. Interestingly, the Mu-A-mediated increases in cell shortening and in the rate of contraction were completely suppressed by pre-treatment with the PKC inhibitor GF109203X. The stimulatory effect of Mu-A on ICa,L was not altered by inhibition of PKA (KT5720), G-protein coupled receptors (suramin), or α1-adrenoceptor (prazosin). However, pre-exposure to the PKC inhibitor, GF109203X or chelerythrine, abolished the Mu-A-induced increase in ICa,L. Pre-exposure to the Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 slightly reduced the stimulatory effects on contraction and ICa,L by Mu-A. Phosphorylation of PKC was enhanced by Mu-A in ventricular myocytes. These data suggest that Mu-A increases contraction and ICa,L via PKC in rat ventricular myocytes, and that the PKC-mediated responses in the presence of Mu-A may be partly mediated by CaMKII.
Jang Hoon Kim, Abubaker M. A. Morgan, Bui Huu Tai, Doan Thi Van, Nguyen Manh Cuong, and Young Ho Kim
Journal of Enzyme Inhibition and Medicinal Chemistry, ISSN: 14756366, eISSN: 14756374, Pages: 640-644, Published: 3 July 2016 Informa UK Limited
Abstract The aim of this study is to search for soluble epoxide hydrolase (sEH) inhibitors from natural plants, bioassay-guided fractionation of lipophilic n-hexane and chloroform layers of an extract of the aerial parts of Glycosmis stenocarpa led to the isolation of 12 compounds (1–12) including murrayafoline-A (1), isomahanine (2), bisisomahanine (3), saropeptate (4), (24 S)-ergost-4-en-3,6-dione (5), stigmasta-4-en-3,6-dion (6), stigmast-4-en-3-one (7), β-sitosterol (8), 24-methylpollinastanol (9), trans-phytol (10), neosarmentol III (11) and (+)-epiloliolide (12). Their structures were elucidated on the basis of spectroscopic data. Among them, neosarmentol III (11) was isolated from nature for the first time. All the isolated compounds were evaluated for their inhibitory activity against sEH. Among isolated carbazole-type compounds, isomahanine (2) and bisisomahanine (3) were identified as a potent inhibitor of sEH, with IC50 values of 22.5 ± 1.7 and 7.7 ± 1.2 µM, respectively. Moreover, the inhibitory action of 2 and 3 represented mixed-type enzyme inhibition.
Pham Ngoc Khanh, Ho Viet Duc, Tran Thu Huong, Ninh The Son, Vu Thi Ha, Doan Thi Van, Bui Huu Tai, Ji Eun Kim, Ah Reum Jo, Young Ho Kim, and Nguyen Manh Cuong
Fitoterapia, ISSN: 0367326X, eISSN: 18736971, Volume: 109, Pages: 39-44, Published: 1 March 2016 Elsevier BV
Phytochemical analysis of the leaves and stems of Callistemon citrinus (Curtis) Skeels led to the isolation of two new alkylphloroglucinols, gallomyrtucommulone E and F (1 and 2), along with four other known alkylphloroglucinol derivatives, gallomyrtucommulone A (3), endoperoxide G3 (4), myrtucommulone B (5), callistenone B (6) and five known triterpenoids, including betulinic acid (7), 3β-acetylmorolic acid (8), 3β-hydroxy-urs-11-en-13(28)-olide (9), diospyrolide (10) and ursolic acid (11). The structures of the natural compounds were determined from the spectroscopic evidences including 1D-/2D-NMR and HR-MS spectrometry. All the isolated compounds were assessed for the effects on the sEH inhibitory activity. The acylphloroglucinols myrtucommulone B (5)/callistenone B (6) (in mixture), and two triterpenoids, ursolic acid (11) and 3β-hydroxy-urs-11-en-13(28)-olide (9) displayed strong inhibition of sEH activity, with IC50 values of 0.7, 11.2 and 24.8 μM, respectively.
Nguyen Manh Cuong, Tran Thu Huong, Ninh The Son, To Dao Cuong, Doan Thi Van, Pham Ngoc Khanh, Vu Thi Ha, Nguyen Cong Thuy Tram, Pham Quoc Long, and Young Ho Kim
Chemical and Pharmaceutical Bulletin, ISSN: 00092363, eISSN: 13475223, Pages: 1230-1234, Published: 2016 Pharmaceutical Society of Japan
Two new naphthalene glycosides, morinlongosides A and B (1, 2) and a new iridoid glycoside, morinlongoside C (3), together with four known ones, geniposidic acid (4), (3R)-3-O-[β-D-xylopyranosyl-(1→6)-β-D-glucopyranosyl]-l-octen-3-ol (5), lucidin-3-O-β-primeveroside (6), and morindone-6-O-β-gentiobioside (7), were isolated from the roots of Morinda longissima Y. Z. RUAN. The structures of all isolated compounds (1-7) were elucidated on the basis of spectroscopic data (high resolution (HR)-MS, one and two dimensional (1/2D)-NMR).
S Saponara, M Durante, O Spiga, P Mugnai, G Sgaragli, TT Huong, PN Khanh, NT Son, NM Cuong, and F Fusi
British Journal of Pharmacology, ISSN: 00071188, eISSN: 14765381, Volume: 173, Pages: 292-304, Published: 1 January 2016 Wiley
The carbazole alkaloid murrayafoline A (MuA) enhances contractility and the Ca2+ currents carried by the Cav1.2 channels [ICa1.2] of rat cardiomyocytes. As only few drugs stimulate ICa1.2, this study was designed to analyse the effects of MuA on vascular Cav1.2 channels.
Nguyen Manh Cuong, Tran Thu Huong, Pham Ngoc Khanh, Nguyen Van Tai, Vu Thi Ha, Ninh The Son, Bui Huu Tai, and Young Ho Kim
Chemical and Pharmaceutical Bulletin, ISSN: 00092363, eISSN: 13475223, Pages: 945-949, Published: 1 November 2015 Pharmaceutical Society of Japan
Two new dimeric monoterpene-linked coumarin glucosides, paratrimerins A (1) and B (2), and three known coumarins, 6-(6-hydroxy-3,7-dimethylocta-2,7-dienyl)-7-hydroxycoumarin (3), ostruthin (4), and ninhvanin (5), were isolated from the roots and stems of Paramignya trimera (OLIV.) GUILL. collected in Khanh Hoa province, Vietnam. Compound 1 comprises two 7-O-β-D-glucopyranoside coumarins linked at positions 6,6' via a 1,3,4,4-tetrasubstituted cyclohexene containing a monoterpene bridge, whereas compound 2 is a β-D-apiofuranosyl(1→6)-β-D-glucopyranosyl derivative of 1. The chemical structures of these compounds were determined by one dimensional (1D) and 2D-NMR and high resolution-electrospray ionization (HR-ESI)-MS spectroscopy.
Joo-Hui Han, Yohan Kim, Sang-Hyuk Jung, Jung-Jin Lee, Hyun-Soo Park, Gyu-Yong Song, Nguyen Manh Cuong, Young Ho Kim, and Chang-Seon Myung
Korean Journal of Physiology and Pharmacology, ISSN: 12264512, eISSN: 20933827, Pages: 421-426, Published: 1 September 2015 The Korean Physiological Society and The Korean Society of Pharmacology (KAMJE)
The increased potential for vascular smooth muscle cell (VSMC) growth is a key abnormality in the development of atherosclerosis and post-angioplasty restenosis. Abnormally high activity of platelet-derived growth factor (PDGF) is believed to play a central role in the etiology of these pathophysiological situations. Here, we investigated the anti-proliferative effects and possible mechanism(s) of murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa Guillamin (Rutaceae), on PDGF-BB-stimulated VSMCs. Murrayafoline A inhibited the PDGF-BB-stimulated proliferation of VSMCs in a concentration-dependent manner, as measured using a non-radioactive colorimetric WST-1 assay and direct cell counting. Furthermore, murrayafoline A suppressed the PDGF-BB-stimulated progression through G0/G1 to S phase of the cell cycle, as measured by [3H]-thymidine incorporation assay and cell cycle progression analysis. This anti-proliferative action of murrayafoline A, arresting cell cycle progression at G0/G1 phase in PDGF-BB-stimulated VSMCs, was mediated via down-regulation of the expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, CDK4, and proliferating cell nuclear antigen (PCNA), and the phosphorylation of retinoblastoma protein (pRb). These results indicate that murrayafoline A may be useful in preventing the progression of vascular complications such as restenosis after percutaneous transluminal coronary angioplasty and atherosclerosis.