Christophe Long

Bioactive flavonoids of Tanacetum parthenium revisited

Bio-guided fractionation of an extract from Tanacetum parthenium showing activity as mitotic blocker allowed the isolation and identification of santin 3, jaceidin 2 and centaureidin 1. The latter two closely related flavonols, which, to the best of our knowledge, are isolated here together for the first time, form a mixture difficult to resolve and which is probably the reason for the confusion in the literature regarding their occurrence. Centaureidin 1 had an IC50 of 1 microM while jaceidin 2 and santin 3 were 200 times less active.

Structures and Antimicrobial Activities of Pyridoacridine Alkaloids Isolated from Different Chromotypes of the Ascidian Cystodytes dellechiajei

Three new pentacyclic alkaloids were isolated from different chromotypes of the western Mediterranean ascidian Cystodytes dellechiajei. The purple color morph collected in Catalonia contained the known compounds kuanoniamine D (1), shermilamine B (2), N-deacetylkuanoniamine D (3), and styelsamine C (4) and a new alkaloid named N-deacetylshermilamine B (5). The green color morph collected in the Balearic Islands contained the known compounds 11-hydroxyascididemin (6) and 8,9-dihydro-11-hydroxyascididemin (7) and two new alkaloids named cystodimine A (8) and cystodimine B (9). The blue color morph collected in Catalonia yielded the known compound ascididemin (10). The structures of all compounds were elucidated on the basis of spectroscopic data, mainly 1D and 2D NMR data. The antimicrobial potential of the pyridoacridine alkaloids isolated from each color morph was evaluated and compared.

Additional cytotoxic pyridoacridine alkaloids from the ascidian Cystodytes violatinctus and biogenetic considerations.

The extraction and purification of the bioactive extract of Cystodytes violatinctus (Solomon Islands) led to the isolation and identification of six pyridoacridine alkaloids. The structures of four new members of this family, shermilamine F (1), dehydrokuanoniamine F (2), and arnoamines C (3) and D (4), were elucidated on the basis of NMR and MS data and by comparison with data of known compounds isolated from this genus. A general hypothetical biogenetic pathway is then proposed for pyridoacridine alkaloids that contain a fused pyrrole ring. Comparison of the biological properties of the isolated alkaloids is also discussed.

Design and synthesis of new non nucleoside inhibitors of DNMT3A.

DNA methylation, an epigenetic modification regulating gene expression, is a promising target in cancer. In an effort to identify new non nucleosidic inhibitors of DNA methyltransferases, the enzymes responsible for DNA methylation, we carried out a high-throughput screening of 66,000 chemical compounds based on an enzymatic assay against catalytic DNMT3A. A family of propiophenone derivatives was identified. After chemical optimization and structure activity relationship studies, a new inhibitor (33) was obtained with an EC50 of 2.1 μM against DNMT3A. The mechanism of inhibition of the compound was investigated as it forms a reactive Michael acceptor group in situ. Thereby, the Michael acceptor 20 was identified. This compound was further characterized for its biological activity in cancer cells.

Dichapetalins from Dichapetalum species and their cytotoxic properties

Six dichapetalins named dichapetalins N-S were isolated from Dichapetalum mombuttense, Dichapetalum zenkeri and Dichapetalum leucosia. They were accompanied in the same plants by the known dichapetalins A, B, C, I, L and M. The structures of the compounds were elucidated by 1D and 2D NMR experiments and mass spectrometry. They all possessed the dammarane skeleton substituted at position C-3 by a C6-C2 unit forming a 2-phenylpyran moiety. All contained a lactone ring in the side chain except dichapetalins O, Q and R, in which this ring was replaced by a lactol. Dichapetalin Q and R were also the first dichapetalins bearing a tertiary methyl and a double bond instead of the cyclopropane of the dammaranes. All these compounds were assayed against cancer cell lines HCT116 and WM 266-4 and displayed cytotoxic and anti-proliferative activities in the 10(-6) to 10(-8)M range.

Meroterpenes from Dichrostachys cinerea Inhibit Protein Farnesyl Transferase Activity

Eighteen new meroterpene derivatives, dichrostachines A-R (1-18), have been isolated from the root and stem barks of Dichrostachys cinerea, and their structures determined by spectroscopic means and molecular modeling. From a biosynthetic standpoint these compounds arise from a Diels-Alder reaction between a labdane diene of the raimonol type and a flavonoid B-ring-derived quinone. The hypothesis was tested by the partial synthesis of similar compounds by simply mixing methyl communate and a synthetic flavonoid quinone. The hemisynthetic compounds were shown by NMR to have configurations different from those of the natural products, thus allowing a refinement of the biosynthesis hypothesis. Most of the compounds were assayed for their ability to inhibit the enzyme protein farnesyl transferase. The most active compounds exhibited IC50 and cytotoxicity values in the 1 microM range.

Alkylated Isocoumarins from Pituranthos Scoparius

Two isocoumarins have been isolated from the ethyl acetate extract of the root of Pituranthos scoparius: 3-n-propyl-5-methoxy-6-hydroxy-isocoumarin and 3-n-propyl-5,7-dimethoxy-6-hydroxy-isocoumarin. Their structures were assigned by spectral analysis.

Cytotoxic triterpenoid saponins from the stem bark of Antonia ovata.

Phytochemical investigation of the MeOH extract of the stem bark of Antonia ovata led to the isolation of four triterpenoid saponins, along with eleven known compounds. Their structures were established by extensive 1D and 2D NMR, as well as HR-MS analysis and acid hydrolysis. All isolated saponins contained the same tetrasaccharide chain O-beta-d-xylopyranosyl-(1-->2)-O-beta-d-glucopyranosyl-(1-->3)-O-[beta-d-glucopyranosyl-(1-->2)]-beta-d-glucuropyranoside linked to C-3 of esterified derivatives of R(1)-barrigenol, A(1)-barrigenol, barringtogenol C, or camelliagenin. Biological evaluation of the compounds against KB cell line revealed a potent cytotoxic activity with IC(50) values ranging from 3.1 to 6.6microM. The known compounds were found to be inactive at 10microg/ml concentration.

Anticancer activity of koningic acid and semisynthetic derivatives

A screening program aimed at discovering novel anticancer agents based on natural products led to the selection of koningic acid (KA), known as a potent inhibitor of glycolysis. A method was set up to produce this fungal sesquiterpene lactone in large quantities by fermentation, thus allowing (i) an extensive analysis of its anticancer potential in vitro and in vivo and (ii) the semi-synthesis of analogues to delineate structure-activity relationships. KA was characterized as a potent, but non-selective cytotoxic agent, active under both normoxic and hypoxic conditions and inactive in the A549 lung cancer xenograft model. According to our SAR, the acidic group could be replaced to keep bioactivity but an intact epoxide is essential.

New methylated flavonol glucosides from Fumana montana Pomel

Three new methylated flavonol glucosides: 3-methoxy-7-O-β-(6″-galloylgluco-pyranoside) quercetin (1), 3,4′-dimethoxy-7-O-β-(6″-galloyl-glucopyranoside) quercetin (2) and 3-methoxy-7-O-β-(6″-galloylgluco-pyranoside) kaempferol (3), in addition to six known flavonols, were isolated from the ethyl acetate extract of Fumana montana Pomel. Their structures were assigned by spectroscopic methods.