Antioxidant, antibacterial, cytotoxic, and apoptotic activity of stem bark extracts of Cephalotaxus griffithii Hook. f

<p>Abstract</p> <p>Background</p> <p><it>Cephalotaxus </it>spp. are known to possess various therapeutic potentials. <it>Cephalotaxus griffithii</it>, however, has not been evaluated for its biological potential. The reason may be the remoteness and inaccessibility of the habitat where it is distributed. The main aim of this study was to: (1) evaluate multiple biological potentials of stem bark of <it>C. griffithii</it>, and (2) identify solvent extract of stem bark of <it>C. griffithii </it>to find the one with the highest specific biological activity.</p> <p>Methods</p> <p>Dried powder of stem bark of <it>C. griffithii </it>was exhaustively extracted serially by soaking in petroleum ether, acetone and methanol to fractionate the chemical constituents into individual fractions or extracts. The extracts were tested for total phenolic and flavonoid content, antioxidant (DPPH radical scavenging, superoxide radical scavenging, and reducing power models), antibacterial (disc diffusion assay on six bacterial strains), cytotoxic (MTT assay on HeLa cells), and apoptotic activity (fluorescence microscopy, DNA fragmentation assay, and flow cytometry on HeLa cells).</p> <p>Results</p> <p>Among the three extracts of stem bark of <it>C. griffithii</it>, the acetone extract contained the highest amount of total phenolics and flavonoids and showed maximum antioxidant, antibacterial, cytotoxic (IC₅₀of 35.5 ± 0.6 μg/ml; P < 0.05), and apoptotic (46.3 ± 3.6% sub-G0/G1 population; P < 0.05) activity, followed by the methanol and petroleum ether extracts. However, there was no significant difference observed in IC₅₀values (DPPH scavenging assay) of the acetone and methanol extracts and the positive control (ascorbic acid). In contrast, superoxide radical scavenging assay-based antioxidant activity (IC₅₀) of the acetone and methanol extracts was significantly lower than the positive control (P < 0.05). Correlation analysis suggested that phenolic and flavonoid content present in stem bark of <it>C. griffithii </it>extracts was responsible for the high antioxidant, cytotoxic, and apoptotic activity (P < 0.05).</p> <p>Conclusions</p> <p>Stem bark of <it>C. griffithii </it>has multiple biological effects. These results call for further chemical characterization of acetone extract of stem bark of <it>C. griffithii </it>for specific bioactivity.</p

Structure and in vitro antitumor activity evaluation of brominated diterpenes from the red alga Sphaerococcus coronopifolius

A novel bromoditerpene methyl ketone (1), two new bromoditerpene alcohols featuring a neodolastane (2), and a bromocorodienol skeleton (3), along with 13 previously reported metabolites (4-16) were isolated from the organic extract of Sphaerococcus coronopifolius collected from the rocky coasts of Corfu island in the Ionian Sea. The structures of the new natural products, as well as their relative stereochemistry, were elaborated on the basis of extensive spectral analysis, including 2D NMR experiments. The absolute stereochemistry of metabolite 3 was determined using the modified Mosher&apos;s method. The isolated metabolites were evaluated for their antitumoral activity against four human apoptosis-resistant (U373, A549, SKMEL-28, OE21) and two human apoptosis-sensitive (PC-3, LoVo) cancer cell lines with IC50 in vitro growth inhibitory concentrations in the range 3-100 μM. © 2009 Elsevier Ltd. All rights reserved

Lycorine and its Derivatives for Anticancer Drug Design

Amaryllidaceae alkaloids are extensively studied for their biological activities in several pharmaceutical areas, including, for example, Alzheimer's disease for which galanthamine has already reached the market. Among this chemical family, lycorine displays very promising anti-tumor properties. This review first focuses on the chemical diversity of natural and synthetic analogues of lycorine and their metabolites, and then on mechanisms of action and biological targets through which lycorine and its derivatives display their anti-tumor activity. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer agent

N-Aryl-N'-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: screening, synthesis of simplified derivatives, and structure-activity relationship analysis.

A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three human high-grade glioma cell lines: U373, T98G, and Hs683. Significant in vitro growth inhibitory activity was observed with 2,2-dimethylchroman-type nitro-substituted phenylthioureas, such as compounds 4o and 4p. Interestingly, most tested phenylureas were found to be slightly less active, but more cell selective (normal versus tumor glial cells, such as 3d, 3e, and 3g), thus less toxic, than the corresponding phenylthioureas. No significant differences were observed in terms of chroman-derivative-induced growth inhibitory effects between glioma cells sensitive to pro-apoptotic stimuli (Hs683 glioma cells) and glioma cells associated with various levels of resistance to pro-apoptotic stimuli (U373 and T98G glioma cells), a feature that suggests non-apoptotic-mediated growth inhibition. Flow cytometry analyses confirmed the absence of pro-apoptotic effects for phenylthioureas and phenylureas when analyzed in U373 glioma cells and demonstrated U373 cell cycle arrest in the G0/G1 phase. Computer-assisted phase-contrast videomicroscopy revealed that 3d and 3g displayed cytostatic effects, while 3e displayed cytotoxic ones. As a result, this work identified phenylurea-type 2,2-dimethylchromans as a new class of antitumor agents to be further explored for an innovative therapeutic approach for high-grade glioma and/or for a possible new mechanism of action

Bulbispermine: A Crinine-Type Amaryllidaceae Alkaloid Exhibiting Cytostatic Activity toward Apoptosis-Resistant Glioma Cells

The Amaryllidaceae alkaloid bulbispermine was derivatized to produce a small group of synthetic analogues. These, together with bulbispermine's natural crinine-type congeners, were evaluated invitro against a panel of cancer cell lines with various levels of resistance to pro-apoptotic stimuli. Bulbispermine, haemanthamine, and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimetric assay. Among the synthetic bulbispermine analogues, only the C1,C2-dicarbamate derivative exhibited notable growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apoptosis sensitivity criterion; they displayed similar potencies in both cell types, indicating that the induction of apoptosis is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bulbispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from rigidification of the actin cytoskeleton. These findings lead us to argue that crinine-type alkaloids are potentially useful drug leads for the treatment of apoptosis-resistant cancers and glioblastoma in particular. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Structural simplification of bioactive natural products with multicomponent synthesis. 3. Fused uracil-containing heterocycles as novel topoisomerase-targeting agents.

After the initial discovery of antiproliferative and apoptosis-inducing properties of a camptothecin-inspired pentacycle based on a 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine scaffold, a library of its analogues as well as their oxidized planar counterparts were prepared utilizing a practical multicomponent synthetic protocol. The synthesized compounds exhibited submicromolar to low micromolar antiproliferative potencies toward a panel of human cancer cell lines. Biochemical experiments are consistent with the dihydropyridine library members undergoing intracellular oxidation to the corresponding planar pyridines, which then inhibit topoisomerase II activity, leading to inhibition of proliferation and cell death. Because of facile synthetic preparation and promising antitopoisomerase activity, both the dihydropyridine and planar pyridine-based compounds represent a convenient starting point for anticancer drug discovery.Journal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Novel trisubstituted harmine derivatives with original in vitro anticancer activity.

To overcome the intrinsic resistance of cancer cells to apoptotic stimuli, we designed and synthesized approximately 50 novel β-carbolines structurally related to harmine. Harmine is known for its anticancer properties and is a DYRK1A inhibitor. Of the synthesized compounds, the most active in terms of growth inhibition of five cancer cell lines are cytostatic and approximately 100 times more potent than harmine but demonstrated no DYRK1A inhibitory activity. These novel β-carbolines display similar growth inhibitory activity in cancer cells that are sensitive and resistant to apoptotic stimuli. Using ChemGPS-NP, we found that the more active β-carbolines are all more lipophilic and larger than the less active compounds. Lastly, on the basis of the NCI human tumor cell line anticancer drug screen and the NCI COMPARE algorithm, it appears that some of these compounds, including 5a and 5k, seem to act as protein synthesis inhibitors. © 2012 American Chemical Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Sequestered fulvinol-related polyacetylenes in Peltodoris atromaculata

The Mediterranean dorid nudibranch Peltodoris atromaculata that had been collected while feeding on Haliclona fulva was shown to sequester long-chain fulvinol-like polyacetylene metabolites (compounds 2-5) from the prey. They were isolated along with previously reported bromorenierins from the diethyl ether extracts of both the mollusk and the sponge. Their structures were elucidated by NMR spectroscopy and tandem FABMS analysis. Compound 5 exhibited in vitro growth inhibitory effects against the SKMEL-28 melanoma cell line. © 2014 The American Chemical Society and American Society of Pharmacognosy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe