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International audience; The protein kinase CDK5 (cyclin-dependent kinase 5) is activated through its association with a cyclin-like protein p35 or p39. In pathological conditions (such as Alzheimer's disease and various other neuropathies), truncation of p35 leads to the appearance of the p25 protein. The interaction of p25 with CDK5 up-regulates the kinase activity and modifies the substrate specificity. ATP-mimetic inhibitors of CDK5 have already been developed. However, the lack of selectivity of such inhibitors is often a matter of concern. An alternative approach can be used to identify highly specific inhibitors that disrupt protein interactions involving protein kinases. We have developed a bioluminescence resonance energy transfer (BRET)-based screening assay in yeast to discover protein-protein interaction inhibitors (P2I2). Here, we present the first use of BRET in yeast for the screening of small molecule libraries. This screening campaign led to the discovery of one molecule that prevents the interaction between CDK5 and p25, thus inhibiting the protein kinase activity. This molecule may give rise to high-specificity drug candidates.

The first enantioselective chiral phosphoric acid-catalyzed transfer hydrogenation of N-aryl-ortho-hydroxybenzophenone ketimines using a Hantzsch ester as hydrogen source was developed to afford, after removal of the N-aryl group, the corresponding chiral diarylmethylamines in high yields and enantioselectivities.

International audience; Faced with declining soil-water potential, plants synthesize abscisic acid (ABA), which then triggers stomatal closure to conserve tissue moisture. Closed stomates, however, also create several physiological dilemmas. Among these, the large CO2 influx required for net photosynthesis will be disrupted. Depleting CO2 in the plant will in turn bias stomatal opening by suppressing ABA sensitivity, which then aggravates transpiration further. We have investigated the molecular basis of how C3 plants resolve this H2 O-CO2 conflicting priority created by stomatal closure. Here, we have identified in Arabidopsis thaliana an early drought-induced spermidine spermine-N(1) -acetyltransferase homolog, which can slow ABA-mediated stomatal closure. Evidence from genetic, biochemical and physiological analyses has revealed that this protein does so by acetylating the metabolite 1,3-diaminopropane (DAP), thereby turning on the latter's intrinsic activity. Acetylated DAP triggers plasma membrane electrical and ion transport properties in an opposite way to those by ABA. Thus in adapting to low soil-water availability, acetyl-DAP could refrain stomates from complete closure to sustain CO2 diffusion to photosynthetic tissues.

International audience; Investigation of an EtOAc extract of the bark of Libocedrus chevalieri led to the isolation of a new cytotoxic lignan, 5-methoxy-4-epipodophyllotoxin (1), and three known podophyllotoxin analogues, 5-methoxypodophyllotoxin, 5-methoxypodophyllotoxin-4-O-beta-D-glucoside, and podophyllotoxin-4-O-beta-D-glucoside. Six sesquiterpenoids and a diterpenoid were also obtained. Of these, compounds 2-4 are new sesquiterpenoids, named libocedrines A-C, and 3beta-hydroxyilicic alcohol was isolated for the first time from a higher plant. Structures of the new compounds were determined on the basis of spectroscopic methods. Cytotoxicity of the isolated compounds against KB and L1210 cells and their effects on tubulin assembly were evaluated.

The chemical investigation of the EtOAc extract of the bark of Meiogyne cylindrocarpa led to the isolation of two enyne- and five enediyne- γ -lactones, sapranthins A–G ( 1 – 7 ), of which six were new. They were identified by mass spectrometry, extensive one- and two-dimensional NMR spectroscopy and through comparison with data reported in the literature. Sapranthins B, C and E ( 2 , 3 and 5 , respectively) showed a weak cytotoxic activity on L1210 with IC 50 values comprised between 8.1 and 18.0 μM.

Transfer hydrogenation of title ketimines (I) with Hantzsch ester proceeds efficiently in the presence of a chiral BINOL-derived phosphoric acid catalyst to give the corresponding diarylmethylamines (II) in good yields and enantioselectivities (up to 91% e.e.).

Unprotected substrates are converted in a highly efficient manner concerning yields and enantioselectivities.

In an effort to find potent inhibitors of the antiapoptotic protein Bcl-xL, a systematic in vitro evaluation was undertaken on 1470 Malaysian plant extracts. The ethyl acetate extract obtained from the bark of Meiogyne cylindrocarpa was selected for its interaction with the Bcl-xL/Bak association. Bioassay-guided purification of this species led to the isolation of two new dimeric sesquiterpenoids (1 and 2) possessing an unprecedented substituted cis-decalin carbon skeleton. Meiogynin A (1) showed the strongest activity with a K(i) of 10.8 +/- 3.1 microM.

Two new drimanes were isolated and characterized from the bark of Zygogynum baillonii, an endemic New-Caledonian tree of the Winteraceae family. One of it shows a significant cytotoxic activity. In order to define structure–activity relationships, analogues were synthesized and their cytotoxicity was evaluated.

Two new drimanes were isolated and characterized from the bark of Zygogynum baillonii, an endemic New-Caledonian tree of the Winteraceae family. One of it shows a significant cytotoxic activity. In order to define structure–activity relationships, analogues were synthesized and their cytotoxicity was evaluated.

International audience; Bioassay guided purification of the ethanolic extract of the bark of New Caledonian Pittosporum pancheri Brongn. and Gris (Pittosporaceae) led to the isolation and characterization of two new farnesyl monoglycosides, pancherins A and B. The structure of these compounds were determined on the basis of spectroscopic studies. The new compounds displayed a significant activity in the in vitro cytotoxic assay against KB cancer cell line, and pancherin A inhibits weakly farnesyl protein transferase.

International audience; The first enantioselective chiral phosphoric acid-catalyzed transfer hydrogenation of unprotected ortho-hydroxyaryl alkyl N-H ketimines using Hantszch di-tert-butyl ester as a reductant is reported. A variety of ortho-hydroxybenzylamines were obtained in good to excellent yields and enantiomeric excesses.