[Show abstract][Hide abstract] ABSTRACT: In the present study, the cytotoxicity of 30 diterpenoids with an abietane or a halimane skeleton was determined against five human tumor cell lines (HL-60, U937, Molt-3, SK-MEL-1, and MCF-7). Diterpenoids containing an abietane skeleton including taxodone (1) and taxodione (2), as well as the semisynthetic derivatives 12, 14, 15, 17, and 22, were the most cytotoxic compounds for human leukemia cells. Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-xL did not confer resistance to abietane diterpene-induced cytotoxicity. Studies performed on HL-60 cells indicated that growth inhibition triggered by compounds 1, 12, 14, and 15 was caused by induction of apoptosis. This was prevented by the nonspecific caspase inhibitor Z-VAD-FMK and, in the case of compounds 14 and 15, reduced by the selective caspase-8 inhibitor Z-IETD-FMK. Cell death induced by these abietane diterpenes was found to be associated with the release of mitochondrial proteins, including cytochrome c, Smac/DIABLO, and AIF (apoptosis-inducing factor), accompanied by dissipation of the mitochondrial membrane potential (ΔΨ), and modulated by inhibition of extracellular signal-regulated kinases signaling and the p38 mitogen-activated protein kinase pathway.
[Show abstract][Hide abstract] ABSTRACT: A new g-lactone named maroccanin (1) together with 5 known compounds: Scopoletin (2); 8a-[2'- hydroxymethyl-2'-butenoyloxy]-dehydromelitensin (3); 11,13-dehydromelitensin (4); 8a-[2'-hydroxymethyl-2'- butenoyloxy]-sonchucarpolide (5) and 5Hα,6Hβ,7Hα,-15-hydroxy-8α-(1',2'-dihydroxyethyl-acryloxy)-elema- 1(2),3(4),11(13)-trien-6,12-olide (6), were isolated from the chloroform soluble part of the aqueous-MeOH extract of the flowering aerial parts of C. maroccana Ball. (Asteraceae), an endemic species of the North of the Sahara. The structures were established by chemical and spectral analysis, mainly HR-ESIMS, HREIMS,UV and NMR experiments (COSY, NOESY, HSQC and HMBC). The compounds 3 and 5 are new for the genus Centaurea.
Records of Natural Products 03/2013; 7(2). · 0.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hybridization of two different bioactive molecules with different mechanism of action is one of the methods that are being adopted to treat cancer. Molecules bearing a thiazolidine-2,4-dione scaffold have been recognized as antineoplastic agents with a broad spectrum of activity against many cancer cell lines. In this manuscript we have described the synthesis and biological evaluation of two series of N-3-substituted-5-arylidene thiazolidine-2,4-diones, bearing the α-bromoacryloylamido moiety at the para- or meta-position on the phenyl of the arylidene portion. We have observed that selected compounds 5a, 5c and 5g suppress proliferation of human myeloid leukaemia HL-60 and U937 cells by triggering morphological changes and internucleosomal DNA fragmentation, which are well-known features of apoptosis. Finally, our results indicated that the investigated compounds induced apoptotic cell death through a mechanism that involved activation of multiple caspases and was also associated with the release of cytochrome c from the mitochondria.
European Journal of Medicinal Chemistry 03/2013; 63C:544-557. DOI:10.1016/j.ejmech.2013.02.030 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Phytochemical research of the aerial parts of Centaurea omphalotricha led to the isolation of three new sesquiterpene lactones, 4'-acetyl cynaropicrin, 4'-acetyl cebellin F and 15-acetyl dehydromelitensin, together with twelve known compounds, seven sesquiterpene lactones, two isoprenoids and three flavonoids. The structures of the new compounds were elucidated by means of extensive 1D and 2D NMR, and MS, and by comparison with reported data in the literature. The effect of sesquiterpene lactones on the viability of the human tumor cell lines HL-60 and U937 was also investigated and 3-acetyl cynaropicrin, and 4'-acetyl cynaropicrin were found to be the most cytotoxic compounds against human leukemia cells with an IC50 values of 2.0 ± 0.9 and 5.1 ± 0.4 µmol L-1, respectively.
Journal of the Brazilian Chemical Society 05/2012; 23(5):977-983. DOI:10.1590/S0103-50532012000500026 · 1.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A variety of spirostan saponins and related glycosides were synthesized and evaluated for their cytotoxicity against the human myeloid leukemia cell line (HL-60). A linear glycosylation strategy allowed for accessing a variety of functionalization patterns at both the spirostanic and the saccharide moieties, which provides new information regarding the structure-cytotoxicity relationship of this family of steroidal glycosides. Intriguing results were achieved with respect to hecogenyl and 5α-hydroxy-laxogenyl β-chacotriosides, turning out to be the former very cytotoxic and the latter no cytotoxic at all. Importantly, the partially pivaloylated β-d-glucosides of 5α-hydroxy-laxogenin were the most potent cytotoxic compounds among all tested glycosides. This comprises the first report on acylated spirostanyl glucosides displaying significant cytotoxicity, and therefore, it opens up new opportunities toward the development of saponin analogues as anticancer agents.
[Show abstract][Hide abstract] ABSTRACT: Two new compounds, the sesquiterpene (1E,5E)-8β-acetoxy-4α-hydroxy-7βH-germacra-1(10),5-dien-14-oic acid (2), and a nor-sesquiterpene, (5E)-8β-acetoxy-4α-hydroxy-7βH-germacr-5-en-10-one (3), were isolated from Pulicaria canariensis ssp. lanata, along with ten known compounds, including the flavonoid 5,3'-dihydroxy-3,7,4'-trimethoxyflavone (4). From Pulicaria burchardii, we isolated seven known compounds; the physical and spectroscopic data of the triterpenoid 3β-hydroxytaraxaster-20-en-30-al (1) are reported. The structures of compounds 1-3 were determined on the basis of HR-MS, and 1D- and 2D-NMR studies. The structure of 2 was corroborated by X-ray crystal diffraction. Cell viability experiments revealed that the semisynthetic flavonoid 4b was the most cytotoxic compound against human leukemia cells, and the cytotoxicity was caused by induction of apoptosis, as determined by microscopy of nuclear changes.
[Show abstract][Hide abstract] ABSTRACT: Induction of apoptosis is a promising strategy that could lead to the discovery of new molecules active in cancer chemotherapy. This property is generally observed when cells are treated with agents that target microtubules, dynamic structures that play a crucial role in cell division. Small molecules such as benzo[b]furans are attractive as inhibitors of tubulin polymerization. A new class of inhibitors of tubulin polymerization based on the 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular skeleton, with the amino group placed at different positions on the benzene ring, were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell-cycle effects. The methoxy substitution pattern on the benzene portion of the benzo[b]furan moiety played an important role in affecting antiproliferative activity. In the series of 5-amino derivatives, the greatest inhibition of cell growth occurred if the methoxy substituent is placed at the C6 position, whereas C7 substitution decreases potency. The most promising compound in this series is 2-(3',4',5'-trimethoxybenzoyl)-3-methyl-5-amino-6-methoxybenzo[b]furan (3 h), which inhibits cancer cell growth at nanomolar concentrations (IC(50) =16-24 nM), and interacts strongly with tubulin by binding to the colchicine site. Sub-G(1) apoptotic cells in cultures of HL-60 and U937 cells were observed by flow cytometric analysis after treatment with 3 h in a concentration-dependent manner. We also show that compound 3 h induces apoptosis by activation of caspase-3, -8, and -9, and this is associated with cytochrome c release from mitochondria. The introduction of an α-bromoacryloyl group increased antiproliferative activity with respect to the parent amino derivatives.
[Show abstract][Hide abstract] ABSTRACT: Novel analogs of spirostan saponins in which the glycosidic bond has been replaced by a triazole linkage are described. For this, a direct oligosaccharide–steroid conjugation approach based on the CuI-catalyzed azide–alkyne 1,3-dipolar cycloaddition was implemented, leading to diverse combinations of saponin analogs with variations in the trisaccharide moiety, the artificial linkage, and the steroid-skeleton functionalization. This ‘click’ process proved great efficiency for the ligation of two bulky building blocks (e.g., chacotriose derivatives and spirostanes bearing axial azides), which enabled the rapid creation of a small library of triazole-based analogs for cytotoxicity evaluation. A molecular modeling study was performed to understand the conformational and electronic differences between a natural saponin and its triazole-based analogs.Graphical abstract
[Show abstract][Hide abstract] ABSTRACT: A new flavone glucoside, apigenin 4'-(6″-methylglucuronide) (1), together with six known compounds, cirsilineol, jaceosidin, melitensin, apigenin, apigenin 7-(6″-methylglucuronide) and prunasin, were isolated from the ethanolic extract of the aerial parts of Centaurea nicaeensis All. var. walliana M. (Asteraceae) collected from Souk-Ahras, eastern Algeria. The structures were established by spectral analysis, mainly HRESI-MS, UV and 2D-NMR experiments (COSY, HSQC and HMBC).
Natural product research 08/2011; 26(3):203-8. DOI:10.1080/14786419.2010.534995 · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The hepatoprotective effect of aqueous ethanol extract of Artimesia monosperma aerial parts was investigated against carbon tetrachloride-induced acute hepatotoxicity in rat. The hepatoprotective activity of A. monosperma was evaluated by determination of liver enzyme markers in the serum (aspartat amino transferase AST; serum alanine transaminase ALT and alkaline phosphatase ALP). The histopathological studies were also carried out to support the above parameters. Oral administration of A. monosperma (100 and 200 mg/kg) markedly reduced the elevated values of AST, ALT and ALP caused by CCl 4 treatment. Glutathione (GSH) significantly decreases in the group treated with CCl 4 . A. monosperma (two doses) and silymarin significantly increased GSH levels when they administrated with CCl 4 . However, silymarin normalized liver enzymes and increased GSH levels than A. monosperma (two doses) when compared with the control group. Histopathological results revealed that A. monosperma treatment with its two doses exhibited almost normal architecture, compared to CCl 4 -treated group. Image analysis of liver revealed a marked reduction in liver damage area after treatment with A. monosperma (100 or 200 mg/kg) and silymarin compared with CCl 4 -treated group. A phytochemical study of A. monosprema resulted in the isolation of a quercetin 3-O-β-glucopyranoside; quercetin 5-O-β-glucopyranoside; isorhamnetin 3-O-β-glucopyranoside; 5, 4' -dihydroxy 6, 7-dimethoxy flavone; 5, 3' -dihydroxy 6, 7, 4'-trimethoxy flavone; 5, 7, 3' -trihydroxy 3, 6, 4' -trimethoxy flavone; quercetin and isorhamnetin. Structures of the isolated compounds were established by chromatography, UV and 1D/2D 1 H' 13 C spectroscopy. Hepatoprotective effect of A. momosperma is probably due to combined effect of flavonoids.
[Show abstract][Hide abstract] ABSTRACT: One diterpenoid, horminone 1, two flavonoid glycosides, apigenin-7-O-(6″-E-p-coumaroyl)-β-d-glucopyranoside 2, isoscutellarein-7-O-(6″′-O-acetyl-β-d-allopyranosyl-(1→2)-β-d-glucopyranoside) 3, were isolated from n-butanolic extract of the aerial parts of Stachys mialhesi de Noé (BESM). Their structures were established on the basis of physical and spectroscopic analysis, and by comparison with the literature data. Antioxidant activity of this extract and the compound 3 was evaluated by the use of the Electron Spin Resonance method in order to visualize the inhibition of the DPPH radical. In this study, we also investigated the anti-inflammatory, anti-ulcer and antinociceptive activities of the BESM in experimental animal models at different doses. Our results showed that the BESM showed a strongest antioxidant activity. It decreased acetic acid induced writhing times; inhibited carrageenan-induced hind paw edema. All of these results suggested that the BESM possesses significant antioxidant, antinociceptive and anti-inflammatory activities.
Arabian Journal of Chemistry 03/2011; 177. DOI:10.1016/j.arabjc.2011.03.005 · 3.73 Impact Factor