Guillaume Bernadat

Spontaneous Biomimetic Formation of (±)-Dictazole B under Irradiation with Artificial Sunlight†

Guided by biosynthetic considerations, the total synthesis of dictazole B is reported for the first time. Experimental evidence for an easy access to challenging cyclobutane alkaloids of marine origin, which are often postulated to be biosynthetic precursors of more complex structures, is provided.

Synthesis of a 3-(α-Styryl)benzo[b]-thiophene Library via Bromocyclization of Alkynes and Palladium-Catalyzed Tosylhydrazones Cross-Couplings: Evaluation as Antitubulin Agents

A library of functionalized 3-(α-styryl)-benzo[b]thiophenes, endowed with a high level of molecular diversity, was efficiently synthesized by applying a synthetic sequence that allowed introduction of various substituents on aromatic A, B, and C-rings. The strategy developed involves the synthesis of 3-bromobenzo[b]thiophene derivatives through a bromocyclization step of methylthio-containing alkynes using N-methylpyrrolidin-2-one hydrotribromide reagent (MPHT). Further coupling of 3-bromobenzothiophenes under palladium-catalysis with N-tosylhydrazones efficiently furnished 2-aryl-3-(α-styryl)benzo[b]thiophene derivatives. The antiproliferative properties of target compounds were studied. Among them, compound 5m has demonstrated submicromolar cytotoxic activity against HCT-116 cell line, and inhibited the polymerization of tubulin at micromolar level comparable to that of CA-4.

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.

A one-pot synthesis of 3-trifluoromethyl-2-isoxazolines from trifluoromethyl aldoxime

Summary Functionalized 3-trifluoromethyl-2-isoxazolines and 3-trifluoromethylisoxazoles were easily prepared from trifluoromethyl aldoxime 2 under mild conditions by using DIB as oxidant. Theoretical studies of the reactivity of trifluoroacetonitrile oxide 4 toward olefins and alkynes were carried out. The 3-trifluoromethyl-2-isoxazolines were ring-opened with NaBH4 and NiCl2 to yield the corresponding trifluoromethylated γ-amino alcohols.

IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

A series of novel isocombretaquinazolines (isoCoQ) 4 were quickly prepared by coupling N‐toluenesulfonylhydrazones with 4‐chloroquinazolines under palladium catalysis. These compounds, which can be regarded as isocombretastatin A‐4 (isoCA‐4) analogues that lack the 3,4,5‐trimethoxyphenyl ring, displayed nanomolar‐level cytotoxicity against various human cancer cell lines and were observed to effectively inhibit tubulin polymerization. The isoCoQ compounds 2‐methoxy‐5‐(1‐(2‐methylquinazolin‐4‐yl)vinyl)phenol (4 b), 4‐[1‐(3‐fluoro‐4‐methoxyphenyl)vinyl]‐2‐methylquinazoline (4 c), and 2‐methoxy‐5‐(1‐(2‐methylquinazolin‐4‐yl)vinyl)aniline (4 d), which respectively bear the greatest resemblance to isoCA‐4, isoFCA‐4, and isoNH2CA‐4, are able to arrest HCT116 cancer cells in the G2/M cell‐cycle phase at very low concentrations. Preliminary in vitro antivascular assay results show that 4 d is able to disrupt a network of capillary‐like structures formed by human umbilical vein endothelial cells on Matrigel. All these results clearly demonstrate that replacement of the 3,4,5‐trimethoxyphenyl ring of isoCA‐4 with a quinazoline nucleus is a feasible approach toward new and highly promising derivatives with the potential for further development as antitubulin agents.

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.

A Unified Bioinspired “Aplysinopsin Cascade”: Total Synthesis of (±)-Tubastrindole B and Related Biosynthetic Congeners

Applying a biomimetic approach, the first total synthesis of (±)-tubastrindole B is reported herein. This work features a ring-expansion cascade of a dictazole-type precursor into cycloaplysinopsin-type congeners. Moreover, the isolation of a transient biogenetic intermediate represents a milestone in the biosynthetic understanding of this family of marine alkaloids.

Interaction of chemokine receptor CXCR4 in monomeric and dimeric state with its endogenous ligand CXCL12: coarse-grained simulations identify differences

Despite the recent resolutions of the crystal structure of the chemokine receptor CXCR4 in complex with small antagonists or viral chemokine, a description at the molecular level of the interactions between the full-length CXCR4 and its endogenous ligand, the chemokine CXCL12, in relationship with the receptor recognition and activation, is not yet completely elucidated. Moreover, since CXCR4 is able to form dimers, the question of whether the CXCR4–CXCL12 complex has a 1:1 or 2:1 preferential stoichiometry is still an open question. We present here results of coarse-grained protein–protein docking and molecular dynamics simulations of CXCL12 in association with CXCR4 in monomeric and dimeric states. Our proposed models for the 1:1 and 2:1 CXCR4–CXCL12 quaternary structures are consistent with recognition and activation motifs of both partners provided by the available site-directed mutagenesis data. Notably, we observed that in the 2:1 complex, the chemokine N-terminus makes more steady contacts with the receptor residues critical for binding and activation than in the 1:1 structure, suggesting that the 2:1 stoichiometry would favor the receptor signaling activity with respect to the 1:1 association.

Carbonylhydrazide-Based Molecular Tongs Inhibit Wild-Type and Mutated HIV-1 Protease Dimerization

We have designed and synthesized new molecular tongs based on a rigid naphthalene scaffold and evaluated their antidimer activity on HIV-1 protease (PR). We inserted carbonylhydrazide and oligohydrazide (azatide) fragments into their peptidomimetic arms to reduce hydrophobicity and increase metabolic stability. These fragments are designed to disrupt the protein-protein interactions by reproducing the hydrogen bond pattern found in the antiparallel β-sheet formed between the N- and C-ends of the two monomers in the native PR. Kinetic analyses and fluorescent probe binding studies showed that several molecular tongs can inhibit PR dimerization. The best nonpeptidic molecular tongs to date were obtained with an inhibition constant K(id) of 50 nM for PR and 80 nM for the multimutated protease ANAM-11. The PR inhibition was selective, the aspartic proteases renin and pepsin were not inhibited.

Unified biomimetic assembly of voacalgine A and bipleiophylline via divergent oxidative couplings

Bipleiophylline is a highly complex monoterpene indole alkaloid composed of two pleiocarpamine units anchored on an aromatic spacer platform. The synthesis of bipleiophylline is considered as a mountain to climb by the organic chemistry community. Here, a unified oxidative coupling protocol between indole derivatives and 2,3-dihydroxybenzoic acid, mediated by silver oxide, has been developed to produce the core of bipleiophylline. This method also allows the independent preparation of benzofuro[2,3-b]indolenine and isochromano[3,4-b]indolenine scaffolds, depending only on the nature of the aromatic platform used. The procedure has been applied to simple indole derivatives and to more challenging monoterpene indole alkaloids, thereby furnishing natural-product-like structures. The use of scarce pleiocarpamine as the starting indole allows the first syntheses of bipleiophylline and of its biosynthetic precursor, voacalgine A. The structure of the latter has been reassigned in the course of our investigations by 2D NMR and displays an isochromano[3,4-b]indolenine motif instead of a benzofuro[2,3-b]indolenine.