a b s t r a c tThe 'Ulam', a traditional Malay dish, are plants that can be eaten raw, as a form of local salad. The shoots and young leaves of Melicope ptelefolia are among the popular species, believed to be high in nutritional and medicinal values. The metabolomic fingerprinting analysis of the ethanolic extracts of leaves of M. ptelefolia was carried out using 1 H Nuclear Magnetic Resonance (NMR) spectroscopy and multivariate data analysis in order to differentiate young and mature leaves and to evaluate the variation of their chemical composition. Principle component analysis (PCA) of the 1 H NMR spectra showed a clear discrimination between the young and mature leaves extracts by PC3 and PC4. The compounds responsible for the differentiation were identified by comparison of 1 H NMR chemical shifts and qualitative HPLC. The young leaves were found to be richer in fatty acids and the levels of the three marker compounds, p-Ogeranylcoumaric acid, 2,4,6-trihydroxy-3-geranylacetophenone and 2,4,6-trihydroxy-3-prenylacetophenone, were clearly higher. The mature leaves contain higher levels of sugars and glycosidic components.
AimsCurcumin is a lead compound of the rhizomes of Curcuma longa and possess a broad range of pharmacological activities. Chemically, curcumin is 1,3-dicarbonyl class of compound, which exhibits keto-enol tautomerism. Despite of its strong biological properties, curcumin has yet been recommended as a therapeutic agent because of its poor bioavailability.Main methodsA curcumin derivative (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (DK1) was synthesized and its cytotoxicity was tested on breast cancer cell MCF-7 and normal cell MCF-10A using MTT assay. Meanwhile, cell cycle regulation and apoptosis on MCF-7 cell were evaluated using flow cytometry. Regulation of cell cycle and apoptosis related genes expression was investigated by quantitative real time polymerase chain reaction (qRT-PCR), western blot and caspases activity analyses. Activation of oxidative stress on MCF-7 were evaluated by measuring ROS and GSH levels.Key findingsDK1 was found to possess selective cytotoxicity on breast cancer MCF-7 cell than normal MCF-10A cell. Flow cytometry cell cycle and AnnexinV/PI analyses reported that DK1 effectively arrested MCF-7 at G2/M phase and induced apoptosis after 72 h of incubation than curcumin. Upregulation of p53, p21 and downregulation of PLK-1 subsequently promote phosphorylation of CDC2 which were found contributed to the arrest of G2/M phase. Moreover, increased of reactive oxygen species and reduced of antioxidant glutathione level correlate with apoptosis observed with raised of cytochrome c and active caspase 9.SignificanceDK1 was found to be more effective in inducing cell cycle arrest and apoptosis against MCF-7 cell with much higher selectivity index of MCF-10A/MCF-7 than curcumin, which might be contributed by the overexpression of p53 protein.
A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC(50) value of 0.42 μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC(4) with an IC(50) value of 1.80 μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC(50) value of 0.40 μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of -13.45 (electrostatic) and -5.40 kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56Å hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.
The possible mechanisms of action in the antinociceptive activity induced by systemic administration (intraperitoneal, i.p.) of flavokawin B (FKB) were analysed using chemical models of nociception in mice. It was demonstrated that i.p. administration of FKB to the mice at 0.3, 1.0, 3.0 and 10 mg ⁄ kg produced significant dose-related reduction in the number of abdominal constrictions. The antinociception induced by FKB in the acetic acid test was significantly attenuated by i.p. pretreatment of mice with L-arginine, the substrate for nitric oxide synthase or glibenclamide, the ATP-sensitive K + channel inhibitor, but was enhanced by methylene blue, the non-specific guanylyl cyclase inhibitor. FKB also produced dose-dependent inhibition of licking response caused by intraplantar injection of phorbol 12-myristate 13-acetate, a protein kinase C activator (PKC). Together, these data indicate that the NO ⁄ cyclic guanosine monophosphate ⁄ PKC ⁄ ATP-sensitive K + channel pathway possibly participated in the antinociceptive action induced by FKB.Chalcones or 1,3-diaryl-2-propen-1-ones are a well-known class of flavonoids that have been reported to possess both in vitro and in vivo biological activities including antimicrobial, anticancer, antiprotozoal, antiplatelet, antinociceptive and anti-inflammatory [1][2][3][4][5][6]. It has been reported elsewhere that chalcones and their derivatives inhibited the synthesis of nitric oxide (NO), lipoxygenase as well as cyclo-oxygenase activities which constitute the major pro-inflammatory pathways and remain most targeted for anti-inflammatory and antinociceptive drug development [7][8][9][10].In attempts to obtain active derivatives from chalcone that possesses anti-inflammatory and antinociceptive activities, our group previously isolated 6¢-hydroxy-2¢,4¢-dimethoxychalcone or flavokawin B (FKB) from Alpinia nutans Rosc. along with other chalcones such as cardamonin (6), 5,6-dehydrokawain, (-)-pinocembrin, (-)-pinostrobin and 2¢,3¢,4¢,6¢-tetrahydroxychalcone [11]. Recently, we chemically synthesized FKB and demonstrated that systemic administration of FKB exerted potent dose-dependent antinociceptive activity when assessed in the chemical and thermal models of nociception in mice, indicating involvement of the peripheral and central antinociceptive activities [12]. Moreover, in the same study, we demonstrated that the central antinociceptive activity of FKB was not mediated by the activation of opioid receptors. Besides, we also demonstrated that FKB produced marked inhibition of the nociceptive response caused by intraplantar injection of glutamate into mouse hind paw in the glutamate-induced nociception test and perhaps the inhibition of peripheral N-Methyl-D-aspartic acid (NMDA) receptors contributes to the antinociceptive effect of FKB [12]. As activation of the NO cascade is known to take place secondary to NMDA receptor activation and a great deal of evidence has demonstrated the role of NO in various models of nociception [13][14][15][16], this has led to the ...
Bioassay-guided isolation of two new compounds, 3,4-methylenedioxy-3'-O-methyl-4'-O-glucoside ellagic acid (1) and the pteleoellagic acid derivative (2), from the stem bark of Pteleopsis hylodendron is reported along with 3,4-methylenedioxy-3'-O-methyl ellagic acid (3), 3,3'-di-O-methyl ellagic acid (4) and 3,3',4'-tri-O-methyl ellagic acid (5), which were obtained for the first time from this plant. The structures of these compounds were elucidated with the help of spectroscopic studies. Compounds 1 and 4 were found to have significant antioxidant activity, while compounds 1-4 showed antibacterial activity against different pathogenic bacteria.
Naturally occurring anthraquinones, damnacanthal (1) and nordamnacanthal (2) were synthesized with modified reaction steps and investigated for their cytotoxicity against the MCF-7 and K-562 cancer cell lines, respectively. Intermediate analogues 2-bromomethyl-1,3-dimethoxyanthraquinone (5, IC 50 = 5.70 ± 0.21 and 8.50 ± 1.18 μg/mL), 2-hydroxymethyl-1,3-dimethoxyanthraquinone (6, IC 50 = 12.10 ± 0.14 and 14.00 ± 2.13), 2-formyl-1,3-dimethoxyantharquinone (7, IC 50 = 13.10 ± 1.02 and 14.80 ± 0.74), 1,3-dimethoxy-2-methylanthraquinone (4, IC 50 = 9.40 ± 3.51 and 28.40 ± 2.33), and 1,3-dihydroxy-2-methylanthraquinone (3, IC 50 = 25.60 ± 0.42 and 28.40 ± 0.79) also exhibited moderate cytotoxicity against MCF-7 and K-562 cancer cell lines, respectively. Other structurally related compounds like 1,3-dihydroxyanthraquinone (13a, IC 50 = 19.70 ± 0.35 and 14.50 ± 1.28), 1,3-dimethoxyanthraquinone (13b, IC 50 = 6.50 ± 0.66 and 5.90 ± 0.95) were also showed good cytotoxicity. The target compound damnacanthal (1) was found to be the most cytotoxic against the MCF-7 and K-562 cancer cell lines, with OPEN ACCESSMolecules 2013, 18 10043IC 50 values of 3.80 ± 0.57 and 5.50 ± 1.26, respectively. The structures of all compounds were elucidated with the help of detailed spectroscopic techniques.
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