Ignacio Brouard

Synthesis and biological studies of flexible brevetoxin/ciguatoxin models with marked conformational preference

Abstract A comparison of the more active polyether toxins which are selective activators of voltage-sensitive sodium channels (VSSC), indicate that these molecules are mostly flat, with a hinge part around the middle of the molecules and a large curvature at one of the ends. Assuming that the receptor is topographically complementary to the active molecules, from the result reported here we could conclude, that the specific requirements of the receptor region can be achieved by synthetic polyether models based on exclusive participation of oxane/oxepane moieties. A new convergent approach to give oxepene rings via double reduction of methyl diacetals is explored. In searching for biological models to further characterize Na+ channels, our studies show that different voltage-dependent Na+ channels are expressed in the rat uterus and activated by brevetoxin-B. However, selected compound models synthesized in this work, failed to inhibit or activate Na+ channel function.

A facile chemoselective deacetylation in the presence of benzoyl and p-bromobenzoyl groups using p-toluenesulfonic acid

Abstract The acetyl group was chemoselectively cleaved in the presence of p -toluenesulfonic acid ( p -TsOH) in CH 2 Cl 2 /MeOH without affecting the benzoyl (benzoate and p -bromobenzoate) groups and no transesterification product was observed. The treatment of protected carbohydrates with p -TsOH·H 2 O at room temperature usually required a longer reaction time than at 40°C. Other types of sulfonic acid such as 10-camphorsulfonic (CSA) led to similar results.

Multicomponent synthesis of Ugi-type ceramide analogues and neoglycolipids from lipidic isocyanides.

Unique types of ceramide and glycolipid architectures were obtained by means of Ugi reactions incorporating lipidic isocyanides as surrogates of sphingolipids. The multicomponent nature of this approach allowed for a highly efficient assembly process, wherein two of the components provided the lipidic tails while a third one incorporated either the functionality suitable for the conjugation to sugar or the sugar moiety itself. Two dissimilar strategies were implemented: (i) the initial assembly of ceramide analogues followed by glycosylation to produce a glycolipid skeleton and (ii) the one-pot construction of glycolipid frameworks by condensation of lipidic isocyanides either with lipidic amines and oligosaccharidic acids or with fatty acids and oligosaccharidic amines. Whereas both approaches are amenable for accessing analogues of anticancer glycolipids, the latter one proved to have greater potential owing to its more straightforward and efficient character. Overall, the methodology developed shows great promise toward the massive (eventually combinatorial) production of neoglycolipids suitable for biological screening.

New insights into the structure-cytotoxicity relationship of spirostan saponins and related glycosides.

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.

Flavonoids of Campanula alata and their antioxidant activity

0009-3130/11/4606-0968 2011 Springer Science+Business Media, Inc. 1) Laboratoire d Obtention de Substances Therapeutiques (L.O.S.T), Faculte des Sciences Exactes, Universite MentouriConstantine, Campus Chaabat Ersas, 25000 Constantine, Algerie, e-mail: zkabouche@yahoo.com; 2) Instituto de Productos Naturales y Agrobiologia-C.S.I.C.-Instituto Universitario de Bio-Organica “Antonio Gonzalez”, Universidad de La Laguna, Av. Astrofisico F. Sanchez 3, 38206 La Laguna, Tenerife, Spain. Published in Khimiya Prirodnykh Soedinenii, No. 6, pp. 825–826, November–December, 2010. Original article submitted July 15, 2009. Chemistry of Natural Compounds, Vol. 46, No. 6, 2011

A new ceramide from Suillus luteus and its cytotoxic activity against human melanoma cells.

A new phytosphingosine‐type ceramide, suillumide (1), was isolated from the EtOH extract of the basidiomycete Suillus luteus (L.) S.u2005F. Gray, along with ten known compounds: ergosta‐4,6,8(14),22‐tetraen‐3‐one, ergosterol, ergosterol peroxide, suillin, (E)‐3,4,5‐trimethoxycinnamic alcohol, 5α,6α‐epoxyergosta‐8,22‐diene‐3β,7β‐diol, (R)‐1‐palmitoylglycerol, ergosta‐7,9(11),22‐triene‐3β,5α,6β‐triol, cerevisterol, and 4‐hydroxybenzoic acid. The structure of 1 was determined on the basis of spectroscopic and mass‐spectrometric analyses, as well as by chemical methods. Compound 1 and its synthetic diacetyl derivative 2 were tested for their cytotoxic activities against the human melanoma cell line SK‐MEL‐1. Both drugs showed IC50 values of ca. 10u2005μM after 72u2005h of exposure.

Cytotoxic sesquiterpene lactones and other constituents of Centaurea omphalotricha

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.

Synthesis and effects on cell viability of flavonols and 3-methyl ether derivatives on human leukemia cells.

Flavonoids are polyphenolic compounds which display an array of biological activities and are considered potential antitumor agents. Here we evaluated the antiproliferative activity of selected synthetic flavonoids against human leukemia cell lines. We found that 4-bromoflavonol (flavonol 3) was the most potent. This compound inhibited proliferation in a concentration-dependent manner, induced apoptosis and blocked cell cycle progression at the S phase. Cell death was found to be associated with the cleavage and activation of multiple caspases, the activation of the mitogen-activated protein kinase pathway and the up-regulation of two death receptors (death receptor 4 and death receptor 5) for tumor necrosis factor-related apoptosis-inducing ligand. Moreover, combined treatments using 4-bromoflavonol and TRAIL led to an increased cytotoxicity compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer.

Sesquiterpene lactones from Gonospermum gomerae and G. fruticosum and their cytotoxic activities.

Four new sesquiterpene lactones (1-4) and a new sesquiterpene (5) together with 20 known compounds were isolated from two Gonospermum species (G. gomerae Bolle and G. fruticosum Less). Their structures were determined by analysis of spectroscopic data, including 1D and 2D NMR. The cytotoxicity of several new and known natural and semisynthetic sesquiterpene lactones was also assessed against human myeloid leukemia cell lines (HL-60 and U937), human melanoma cells (SK-MEL-1), and human adenocarcinoma (A549).

A chemotaxonomic study of endemic species of genus Tanacetum from the Canary Islands.

Aerial parts of Tanacetum oshanahanii collected at Jardín Canario Viera y Clavijo, Tanacetum ptarmiciflorum collected at Los Moriscos (Tejeda), and Tanacetum ferulaceum var. latipinnum collected at Anden Verde (Agaete) in Gran Canaria, Canary Islands, afforded three sesquiterpenes related to nerolidol and six sesquiterpene lactones whose structures were established on the basis of their spectroscopic data and chemical transformations. In this work we show that this type of sesquiterpene lactones could be used as chemotaxonomic markers. A series of sesquiterpene lactones described in this paper were assessed for cytotoxicity against HL-60 and U937 cancer cell lines. The derivatives 106a and 98a displayed cytotoxic properties showing IC50 values between 5 and 11 μM. Furthermore, we demonstrated that these selected sesquiterpene lactones induce apoptotic cell death in human leukemia cells through a mechanism that involves activation of multiple caspases and moreover cell death was found to be associated with the release of cytochrome c.