Sandrine Ongeri

Discovery of a New Efficient Chiral Ligand for Copper-Catalyzed Enantioselective Michael Additions by High-Throughput Screening of a Parallel Library

A combinatorial library of 125 chiral Schiff base ligands 5 was synthesized with the use of solution-phase parallel synthesis and solid-phase extraction (SPE) techniques to scavenge excess reagents and reaction by-products and avoid chromatography. The synthetic methodology coupled five N-Boc-protected β-amino sulfonyl chlorides 1 a–e with five different amines 2 f–j to give 25 N-Boc sulfonamides 3, which were in turn deprotected and coupled with five salicylaldehydes 4 p–t to give 125 ligands 5 in good yields and of sufficient purity to be used in ligand-catalyzed reactions. These ligands were tested in the copper-catalyzed conjugate addition of dialkyl zinc to cyclic and acyclic enones. A multisubstrate high-throughput screening of the library was performed with an equimolar mixture of 2-cyclohexenone and 2-cycloheptenone (9 and 10, respectively, 0.2 mmol total), with 5.5 mol % ligand 5 (0.011 mmol) and 5 mol % Cu(OTf)2 (OTf= OSO2CF3) (0.010 mmol) in 1:1 toluene/hexane at −20 °C. From the screening of the library, 5 bhr was identified as the best ligand, which yielded 3-ethylcyclohexanone (12) and 3-ethylcycloheptanone (13) in 82 % and 81 % ee, respectively, and complete conversions. Under optimized conditions (2.75 mol % 5 bhr, 2.5 mol % copper(I) triflate, toluene as reaction solvent), improved results were obtained for 12 (90 % ee, 93 % yield) and for 13 (91 % ee, 95 % yield). Selected ligands 5 were also tested in the addition of Me2Zn to 2-cyclohexenone (9, ee up to 79 %), of Et2Zn to 2-cyclopentenone (11, ee up to 80 %) and to acyclic enones 16 and 17 (ee up to 50 %).

Novel fluorinated pseudopeptides as proteasome inhibitors

We have designed novel small inhibitors of rabbit 20S proteasome using a trifluoromethyl-beta-hydrazino acid scaffold. Structural variations influenced their inhibition of the three types of active sites. Proteasome inhibition at the micromolar level was selective, calpain I and cathepsin B were not inhibited.

Optimization of New Chiral Ligands for the Copper‐Catalysed Enantioselective Conjugate Addition of Et2Zn to Nitroolefins by High‐Throughput Screening of a Parallel Library

A library of chiral ligands 5, obtained with a modular building block strategy from the coupling of sulfonyl chlorides 1a−e, amines 2f−j and aldehydes 4p−t, was screened in the enantioselective, copper-catalysed conjugate addition of Et2Zn to aromatic and heteroaromatic nitroolefins 6a−e. A multisubstrate high-throughput screening was realised by performing the addition reactions on an equimolar mixture of substrates 6c−d. Good ligands for the addition reaction to nitroolefins 6a−e (ee’s up to 58%) were identified.

Synthesis and screening of new chiral ligands for the copper-catalysed enantioselective allylic substitution

The synthesis of the new chiral ligands 6ae, 8ae, 9ae, and 11ae starting from the chiral β-[(Boc)amino]sulfonamide 3ae is reported. The β-amino group of 3ae was deprotected and condensed with 3,5-dichlorosalicylaldehyde (4) to yield the known Schiff base 5ae, which was then reduced to the amino compound 6ae (Scheme 3). Alternatively, condensation of the free amino compound with 2-(diphenylphosphanyl)benzaldehyde (7) afforded the imino ligand 8ae which upon reduction yielded the amino ligand 9ae (Scheme 4). The free amino compound derived from 3ae was also coupled with 2-(diphenylphosphanyl)benzoic acid (10) to give ligand 11ae (Scheme 5). These ligands were tested in the copper-catalysed allylic substitution reaction of cinnamyl (=3-phenylprop-2-enyl) phosphate 12 with diethylzinc as a nucleophile. Ligands 5ae, 6ae, 8ae, and 11ae gave excellent ratios (100 : 0) of the SN2′/SN2 products (Scheme 6 and Table 1). Ligand 11ce, identified from the screening of a small library of ligands of general formula 11, promoted the allylic substitution reaction with moderate enantioselectivity (40% for the SN2′ product 13 (Scheme 8 and Table 3)).

Sugar-based peptidomimetics inhibit amyloid β-peptide aggregation

Alzheimers disease is characterized by the oligomerization and amyloid fibril formation of amyloid β-peptide (Aβ). We describe a novel class of small water-soluble Aβ binding peptidomimetics based on two hydrophobic Ala-Val and Val-Leu dipeptides linked to a D-glucopyranosyl scaffold through aminoalkyl and carboxyethyl links in C1 and C6 positions. These compounds combine the targeting of hydrophobic recognition interfaces with an original hydrophilic sugar β-breakage strategy. These molecules were shown, by fluorescence thioflavin-T assays, to dramatically slow down the kinetics of amyloid fibril formation even at a low peptidomimetics to Aβ ratio of 0.1:1. Electron microscopy images revealed that the peptidomimetics efficiently reduced the amount of typical amyloid fibrils. NMR saturation transfer difference experiments indicated that these molecules interact with Aβ aggregated species through their hydrophobic amino acid residues. This inhibition effect was found to be sequence-specific since these molecules did not alter the kinetics of aggregation of another amyloid peptide, IAPP, involved in type 2 diabetes mellitus.

An improved capillary electrophoresis method for in vitro monitoring of the challenging early steps of Aβ1–42 peptide oligomerization: Application to anti-Alzheimer's drug discovery

We report an improved CE method to monitor in vitro the self‐assembly of monomeric amyloid β‐peptide (42 amino acids amyloid β‐peptide, Aβ1–42) and in particular the crucial early steps involved in the formation of the neurotoxic oligomers. In order to start the kinetics from the beginning, sample preparation was optimized to provide samples containing exclusively the monomeric form. The CE method was also improved using a dynamic coating and by reducing the separation distance. Using this method, the disappearance of the monomer as well as the progressive formation of four species during the self‐assembly process can now be monitored and quantified over time. The hydrodynamic radius of the species present at the initial kinetics step was estimated around 1.8 nm by Taylor dispersion analysis while SDS‐PAGE analyses showed the predominance of the monomer. These results confirmed that the Aβ1–42 species present at this initial time was the monomer. Methylene blue, an anti‐Alzheimer disease candidate, was then evaluated. In spite of an oligomerization inhibition, the enhanced disappearance of the Aβ1–42 monomer provoked by methylene blue was demonstrated for the first time. This method, allowing the monomeric and smallest oligomeric species to be monitored, represents a new accurate and precise way to evaluate compounds for drug discovery.

Toward the First Nonpeptidic Molecular Tong Inhibitor of Wild-Type and Mutated HIV-1 Protease Dimerization

Herein we describe the synthesis and HIV‐1 protease (PR) inhibitory activity of 16 new peptidomimetic molecular tongs with a naphthalene scaffold. Their peptidic character was progressively decreased. Two of these molecules exhibited the best dimerization inhibition activity toward HIV‐1 wild‐type and multimutated ANAM‐11 proteases obtained to date for this class of molecules (∼40 nM for wild‐type PR and 100 nM for ANAM‐11 PR). Although the peptidic character of one molecular tong was completely suppressed, the mechanism of inhibition and inhibitory potency toward both proteases were maintained.

α- and β-hydrazino acid-based pseudopeptides inhibit the chymotrypsin-like activity of the eukaryotic 20S proteasome

We describe the synthesis of a library of new pseudopeptides and their inhibitory activity of the rabbit 20S proteasome chymotrypsin-like (ChT-L) activity. We replaced a natural α-amino acid by an α- or a β-hydrazino acid and obtained inhibitors of proteasome up to a submicromolar range (0.7 μM for molecule 24b). Structural variations influenced the inhibition of the ChT-L activity. Models of inhibitor/20S proteasome complexes corroborated the inhibition efficacies obtained by kinetic studies.

Non-Covalent Proteasome Inhibitors

Regulator of a vast array of vital cellular processes including cell-cycle progression, apoptosis and antigen presentation, the proteasome represents a major therapeutic target. Therefore, selective inhibitors of the proteasome are promising candidates to develop new treatments for diseases like inflammation, immune diseases and cancer. For proof, the boronic acid, Bortezomib has been approved for treating incurable multiple myeloma in 2003 and mantle lymphoma in 2006 and five others proteasome inhibitors are currently in clinical trials for treatment of different cancers. These compounds and many described proteasome inhibitors interact covalently with the active site of the enzyme through an electrophilic reactive function. Non-covalent inhibitors, mainly peptides, pseudopeptides and some organic compounds, have been less widely investigated. Devoid of reactive function prone to nucleophilic attack, they could offer the advantage of an improved selectivity, a less excessive reactivity and instability which are often associated with side effects in therapeutics. This review highlights the current state of research in the field of non-covalent proteasome inhibitors.

Synthesis of new triazole-based trifluoromethyl scaffolds.

Summary Trifluoromethyl propargylamines react with various azide derivatives to afford 1,4-disubstituted 1,2,3-triazoles through a Huisgen 1,3-dipolar cycloaddition. The reaction is catalyzed by a Cu(I) species in acetonitrile, and the corresponding products are obtained in good yields. This process thus offers an entry to new trifluoromethyl peptidomimetics as interesting scaffolds.