Corinne Vanucci-Bacqué

Formal total synthesis of (+)-gephyrotoxin.

An efficient formal total synthesis of (+)-gephyrotoxin is described. The key step of our strategy relies on the diastereoselective reduction of a chiral pyrrolidine beta-enamino ester obtained by condensation of ( S)-phenylglycinol on a protected 8-hydroxy-3,6-dioxooctanoate.

Highly Stereoselective trans Addition of π-Type Nucleophiles to a Bicyclic N-Acyliminium Ion – Application to the Synthesis of Indolizidine and Pyrrolizidine Alkaloids

Enantiopure bicyclic 5-ethoxytetrahydropyrrolo[1,2-c]oxazol-3-one 1b was prepared in two steps from the known tosylate 4, which is readily available from (S)-pyroglutamic acid. Trapping of the N-acyliminium ion (I), generated in situ from 1b in the presence of Lewis acid, with various silylated π-type nucleophiles gave rise selectively to trans adducts 2. The usefulness of this stereoselective access to trans-2,5-disubstituted pyrrolidines was illustrated by formal syntheses of 3,5-disubstituted indolizidine toxins, starting from 5-allyltetrahydropyrrolo[1,2-c]oxazol-3-one 2a. Moreover, an enantiodivergent synthesis of the pyrrolizidine alkaloids (+) and (–)-xenovenine was achieved starting from the same chiral building block 2a.

Diaryl ether derivatives as anticancer agents – a review

This review article examines the diaryl ether scaffold found in natural products, related analogs and innovative molecules. It looks at encompassing synthesis, structure–activity relationships (SARs), and studies on biological action, namely in the context of anti-cancer activity. The aim of this review is to show that the diaryl ether scaffold is an invaluable structure for the design of anticancer drugs. It focuses essentially on work published from January 2000 to March 2012.

Synthesis, antioxidant and cytoprotective evaluation of potential antiatherogenic phenolic hydrazones. A structure-activity relationship insight.

A novel series of hydrazones derived from substituted benzaldehydes have been synthesized as potential antiatherogenic agents. Several methods were used for exploring their antioxidant and cytoprotective properties, such as their scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, the inhibition of superoxide anion (O₂(·-)) generation and the measurement of cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS). The cytoprotective efficacy was also evaluated by measuring the cell viability (monitored by the MTT assay) in the presence of cytotoxic oxidized LDL. In this report, we discuss the relationship between the chemical structure of phenolic hydrazones and their antioxidant and cytoprotective activities, for subsequent application as antiatherogenic agents. This SAR study confirms that the phenolic frame is not the only prerequisite for antioxidant activity and N-methylbenzothiazole hydrazone moiety magnifies the dual required properties in two most interesting derivatives.

FORMAL TOTAL SYNTHESIS OF ENANTIOPURE TRICYCLIC (S)-MYRMICARIN ALKALOIDS 217, 215A AND 215B

We described herein a formal synthesis of the enantiopure tricyclic (4aS)-myrmicarin alkaloids 217, 215A and 215B owing to the obtention of a common pyrroloindolizidine intermediate, starting from a chiral cis-(2S,5R)-disubstituted pyrrolidine. An intramolecular one-pot aldolization-crotonization-aromatization process of a diketo indolizidine constitutes the key step for the formation of the pyrrole ring of the target compound.

Total Synthesis of Tedarene A

Tedarene A is a macrocyclic diaryl ether heptanoid isolated from the marine sponge Tedania ignis showing an inhibitory effect against nitric oxide production. The first total synthesis of tedarene A was achieved starting from the commercially available 3-(4-methoxyphenyl)propan-1-ol in nine steps and 15.3% overall yield. The synthetic sequence featured an E,Z-dienic bond introduction and a macrocyclization under Ullman conditions. During the synthesis, the E,E-isomer of tedarene A was also obtained and fully characterized.

Synthesis and evaluation of antioxidant phenolic diaryl hydrazones as potent antiangiogenic agents in atherosclerosis.

A series of bis-hydrazones derived from diaryl and diaryl ether hydroxybenzaldehyde frames 1 and 2 have been synthesized as potential antioxidant and antiangiogenic agents, two properties required to limit atherogenesis and cardiovascular events. These compounds were evaluated for their ability to neutralize free radical formation, to block endothelial cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS), an essential step in atherogenesis, and subsequent toxicity, to prevent angiogenesis evoked by low oxidized LDL concentration (monitored by the formation of capillary tubes on Matrigel) and to inhibit intracellular ROS increase involved in the angiogenic signaling. A structure/activity study has been carried out and finally allowed to select the phenolic diaryl ether hydralazine derivative 2a, sharing all these protective properties, as a promising hit for further development.

Synthesis and biological evaluation of diarylheptanoids as potential antioxidant and anti-inflammatory agents

Reactive oxygen species (ROS) are key signaling molecules and their overproduction plays an important role in the inflammation process, the secretion of inflammatory cytokines such as IL-1β and IL-6 and the progression of inflammatory disorders. Decreasing oxidative stress represents a promising challenge in the design of antioxidant and anti-inflammatory agents. In the present study, a series of new diarylheptanoids containing allylic alcohol, amide, hydantoin or triazole fragments were synthesized and fully characterized. We evaluated the ability of these agents to block the production of intracellular ROS and the subsequent inflammatory events exerted by lipopolysaccharide (LPS) on murine macrophage RAW 264.7. Five diarylheptanoids were found to exhibit the dual required properties.

4-Hydroxynonenal Contributes to Angiogenesis through a Redox-Dependent Sphingolipid Pathway: Prevention by Hydralazine Derivatives

The neovascularization of atherosclerotic lesions is involved in plaque development and may contribute to intraplaque hemorrhage and plaque fragilization and rupture. Among the various proangiogenic agents involved in the neovascularization process, proatherogenic oxidized LDLs (oxLDLs) contribute to the formation of tubes via the generation of sphingosine 1-phosphate (S1P), a major mitogenic and proangiogenic sphingolipid mediator. In this study, we investigated whether 4-hydroxynonenal (4-HNE), an aldehydic lipid oxidation product abundantly present in oxLDLs, contributes to their proangiogenic properties. Immunofluorescence analysis of human atherosclerotic lesions from carotid endarterectomy showed the colocalization of HNE-adducts with CD31, a marker of endothelial cells, suggesting a close relationship between 4-HNE and neovessel formation. In vitro, low 4-HNE concentration (0.5–1 µM) elicited the formation of tubes by human microvascular endothelial cells (HMEC-1), whereas higher concentrations were not angiogenic. The formation of tubes by 4-HNE involved the generation of reactive oxygen species and the activation of the sphingolipid pathway, namely, the neutral type 2 sphingomyelinase and sphingosine kinase-1 (nSMase2/SK-1) pathway, indicating a role for S1P in the angiogenic signaling of 4-HNE. Carbonyl scavengers hydralazine and bisvanillyl-hydralazone inhibited the nSMase2/SK1 pathway activation and the formation of tubes on Matrigel® evoked by 4-HNE. Altogether, these results emphasize the role of 4-HNE in the angiogenic effect of oxLDLs and point out the potential interest of pharmacological carbonyl scavengers to prevent the neovascularization process.